Substituted pyrrolidine amides iii

ABSTRACT

which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.

This application claims priority of European Patent Application No. 19181 203.1, filed Jun. 19, 2019, European Patent Application No. 19 152282.0, filed Jan. 17, 2019, and European Patent Application No. 19 151406.6, filed Jan. 11, 2019, the entire contents of which are herebyincorporated herein by reference.

The invention relates to compounds according to general formula (I)

which act as modulators of the glucocorticoid receptor and can be usedin the treatment and/or prophylaxis of disorders which are at leastpartially mediated by the glucocorticoid receptor.

Glucocorticoids (GC) exert strong anti-inflammatory, immunosuppressiveand disease-modifying therapeutic effects mediated by the glucocorticoidreceptor (GR). They have been widely used to treat inflammatory andimmune diseases for decades and still represent the most effectivetherapy in those conditions. However, chronic GC treatment ofinflammatory diseases such as asthma, rheumatoid arthritis, inflammatorybowel disease, chronic obstructive pulmonary disease, acute respiratorydistress syndrome, cystic fibrosis, osteoarthritis, polymyalgiarheumatica and giant cell arteritis is hampered by GC-associated adverseeffects. These undesired side effects include insulin resistance,diabetes, hypertension, glaucoma, depression, osteoporosis, adrenalsuppression and muscle wasting with osteoporosis and diabetes being themost severe ones from the physician's point of view (Hapgood JP. et al.,Pharmacol Ther. 2016 September; 165: 93-113; Buttgereit F. el al, ClinExp Rheumatol. 2015 July-August; 33(4 Suppl 92):S29-33; Hartmann K. etal, Physiol Rev. 2016 April; 96(2):409-47).

One example of an oral glucocorticoid is prednisone which is frequentlyprescribed for the treatment of several inflammatory disorders (DeBosscher K et al., Trends Pharmacol Sci. 2016 January; 37(1):4-16;Buttgereit F. et al., JAMA. 2016; 315(22):2442-2458). As GC causeadrenal suppression, prednisolone withdrawal symptoms can be severe ifthe drug is discontinued abruptly when all the signs of the disease havedisappeared. Thus gradual GC tapering to physiological doses isfrequently part of treatment protocols to reduce the risk of relapse andother withdrawal symptoms (Liu D. et al., Allergy Asthma Clin Immunol.2013 Aug. 15; 9(1):30). Therefore, there is high medical need for novelpotent anti-inflammatory drugs with less adverse effects.

Recent research has focused on the development of partial agonists orselective glucocorticoid receptor modulators which activate the pathwaysfor the inhibition of inflammation but avoid targeting the pathways thatlead to the GC-associated adverse effects. Most of these effects havebeen demonstrated to be mediated by different GR-dependent genomicmechanisms termed transactivation and transrepression. Theanti-inflammatory actions of GC are mainly attributable to thetransrepression of inflammatory genes while certain side effects arepredominantly mediated via transactivation of several genes. Accordingto the nature of a ligand the GR can be selectively modulated in aspecific conformation which favors transrepression over transactivationresulting in an improved therapeutic benefit (De Bosscher K et al.,Trends Pharmacol Sci. 2016 January; 37(1):4-16). The concept of suchdissociating ligands was already defined about two decades ago andseveral compounds have been identified and were evaluated in preclinicaland clinical testing but none of them has as yet been approved forclinical use.

Compounds which are active as modulators of the glucocorticoid receptorare also known e.g. from WO 2007/122165, WO 2008/076048 and WO2008/043789, WO 2009/035067, WO 2009/142571, WO 2016/046260, and WO2017/034006.

It was an object of the invention to provide novel compounds which aremodulators of the glucocorticoid receptor and which preferably haveadvantages over the compounds of the prior art.

The novel compounds should in particular be suitable for use in thetreatment and/or prophylaxis of disorders or diseases which are at leastpartially mediated by the glucocorticoid receptor.

This object has been achieved by the subject-matter of the patentclaims.

It was surprisingly found that the compounds according to the inventionare highly potent modulators of the glucocorticoid receptor.

The invention relates to a compound according to general formula (I),

wherein

-   R₁ represents phenyl; —C₁₋₆-alkylene-phenyl; 5 or 6-membered    heteroaryl; —C₁₋₆-alkylene-(5 or 6-membered heteroaryl); or    —C₁₋₁₀-alkyl;-   R_(1′) represents H; —C₁₋₁₀-alkyl; or —C₃₋₁₀-cycloalkyl;-   R₂ represents —C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;    —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-(3 to 7 membered    heterocycloalkyl); —C(═O)—C₁₋₆-alkylene-(3 to 7 membered    heterocycloalkyl); —C(═O)-phenyl; —C(═O)—C₁₋₆-alkylene-phenyl;    —C(═O)-(5 or 6-membered heteroaryl); —C(═O)—C₁₋₆-alkylene-(5 or    6-membered heteroaryl); —S(═O)₁₋₂—C₁₋₁₀-alkyl;    —S(═O)₁₋₂—C₃₋₁₀-cycloalkyl;    —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂-(3 to 7 membered    heterocycloalkyl); —S(═O)₁₋₂—C₁₋₆-alkylene-(3 to 7 membered    heterocycloalkyl); —S(═O)₁₋₂-phenyl; —S(═O)₁₋₂—C₁₋₆-alkylene-phenyl;    —S(═O)₁₋₂-(5 or 6-membered heteroaryl); or    —S(═O)₁₋₂—C₁₋₆-alkylene-(5 or 6-membered heteroaryl);-   R₃ and R_(3′) independently from one another represent H; F; Cl;    —C₁₋₁₀-alkyl; —C₃₋₆-cycloalkyl; —CH₂—C₃₋₆-cycloalkyl; 3 to 7    membered heterocycloalkyl; —CH₂-(3 to 7 membered heterocycloalkyl);    —CH₂-phenyl; or —CH₂-(5 or 6-membered heteroaryl);-   or R₃ and R_(3′) together with the carbon atom to which they are    bound form a C₃₋₁₀-cycloalkyl; or 3 to 7 membered heterocycloalkyl;-   R₄ represents-phenyl; —C₁₋₆-alkylene-phenyl; -5 or 6-membered    heteroaryl; or —C₁₋₆-alkylene-(5 or 6-membered heteroaryl);-   A, X, Y and Z independently from one another represent N or CH;    -   wherein at least one of R₁, R₃ and R_(3′) is not H;    -   wherein —C₁₋₁₀-alkyl and —C₁₋₆-alkylene-in each case        independently from one another is linear or branched, saturated        or unsaturated;    -   wherein —C₁₋₁₀-alkyl, —C₁₋₆-alkylene-, —C₃₋₁₀-cycloalkyl and 3        to 7 membered heterocycloalkyl in each case independently from        one another are unsubstituted or mono- or polysubstituted with        one or more substituents selected from —F; —Cl; —Br; —I; —CN;        —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;        —C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH₂;        —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃;        —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;        —O—C(═O)—C₁₋₆-alkyl; —O—C(═O)—O—C₁₋₆-alkyl;        —O—(CO)—NH(C₁₋₆-alkyl); —O—C(═O)—N(C₁₋₆-alkyl)₂; —O—S(═O)₂—NH₂;        —O—S(═O)₂—NH(C₁₋₆-alkyl); —O—S(═O)₂—N(C₁₋₆-alkyl)₂; —NH₂;        —NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;        —NH—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—NH₂; —NH—C(═O)—NH(C₁₋₆-alkyl);        —NH—C(═O)—N(C₁₋₆-alkyl)₂; —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;        —N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-C(═O)—NH₂;        —N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);        —N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂OH;        NH—S(═O)₂—C₁₋₆-alkyl; —NH—S(═O)₂—O—C₁₋₆-alkyl; —NH—S(═O)₂—NH₂;        —NH—S(═O)₂—NH(C₁₋₆-alkyl); —NH—S(═O)₂N(C₁₋₆-alkyl)₂;        —N(C₁₋₆-alkyl)-S(═O)₂—OH; —N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;        —N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-S(═O)₂—NH₂;        —N(C₁₋₆-alkyl)-S(═O)₂—NH(C₁₋₆-alkyl);        —N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂;        —S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl;        —S(═O)₂—OH; —S(═O)₂—O—C₁₋₆-alkyl; —S(═O)₂—NH₂;        —S(═O)₂—NH(C₁₋₆-alkyl); —S(═O)₂—N(C₁₋₆-alkyl)₂;        —C₃₋₆-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5 or        6-membered heteroaryl; —O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered        heterocycloalkyl); —O-phenyl; —O-(5 or 6-membered heteroaryl);        —C(═O)—C₃₋₆-cycloalkyl; —C(═O)-(3 to 6-membered        heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5 or 6-membered        heteroaryl); —S(═O)₂—(C₃₋₆-cycloalkyl); —S(═O)₂-(3 to 6-membered        heterocycloalkyl); —S(═O)₂-phenyl or —S(═O)₂-(5 or 6-membered        heteroaryl);    -   wherein phenyl and 5 or 6-membered heteroaryl in each case        independently from one another are unsubstituted or mono- or        polysubstituted with one or more substituents selected from —F;        —Cl; —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl;        —CFCl₂; —C₁₋₄-alkylene-CF₃; —C₁₋₄-alkylene-CF₂H;        —C₁₋₄-alkylene-CFH₂; —C(═O)—C₁₋₆-alkyl; —C(═O)—OH;        —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH(OH); —C(═O)—NH₂;        —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃;        —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;        —O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH₂;        —NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;        —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —NH—C(═O)—NH₂;        —NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;        —N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);        —N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂—C₁₋₆-alkyl;        —SCF₃; —S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl;        —S(═O)₂—NH₂; —S(═O)₂—NH(C₁₋₆-alkyl);        —S(═O)₂—N(C₁₋₆-alkyl)₂—C₃₋₆-cycloalkyl;        —C₁₋₄-alkylene-C₃₋₆-cycloalkyl; 3 to 6-membered        heterocycloalkyl; —C₁₋₄-alkylene-(3 to 6-membered        heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl;        in the form of the free compound or a physiologically acceptable        salt thereof, with the proviso that the following compounds are        excluded:-   N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide;-   N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide;-   N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxylic    acid amide;-   N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide;-   N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic    acid amide; and-   N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylic    acid amide.

In a preferred embodiment, the compound according to the invention ispresent in form of the free compound. For the purpose of specification,“free compound” preferably means that the compound according to theinvention is not present in form of a salt. Methods to determine whethera chemical substance is present as the free compound or as a salt areknown to the skilled artisan such as ¹⁴N or ¹⁵N solid state NMR, x-raydiffraction, x-ray powder diffraction, IR, Raman, XPS. ¹H-NMR recordedin solution may also be used to consider the presence of protonation.

In another preferred embodiment, the compound according to the inventionis present in form of a physiologically acceptable salt. For thepurposes of this specification, the term “physiologically acceptablesalt” preferably refers to a salt obtained from a compound according tothe invention and a physiologically acceptable acid or base.

According to the invention, the compound according to the invention maybe present in any possible form including solvates, cocrystals andpolymorphs. For the purposes of this specification, the term “solvate”preferably refers to an adduct of (i) a compound according to theinvention and/or a physiologically acceptable salt thereof with (ii)distinct molecular equivalents of one or more solvents.

Further, the compound according to the invention may be present in formof the racemate, enantiomers, diastereomers, tautomers or any mixturesthereof.

The invention also includes isotopic isomers of a compound of theinvention, wherein at least one atom of the compound is replaced by anisotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium), ³H(tritium), ¹³C and ¹⁴C. Isotopic isomers of a compound of the inventioncan generally be prepared by conventional procedures known to a personskilled in the art.

According to the invention, the terms “—C₁₋₁₀-alkyl”, “—C₁₋₈-alkyl”,“—C₁₋₆-alkyl” and “—C₁₋₄-alkyl” preferably mean acyclic saturated orunsaturated aliphatic (i.e. non-aromatic) hydrocarbon residues, whichcan be linear (i.e. unbranched) or branched and which can beunsubstituted or mono- or polysubstituted (e.g. di- or trisubstituted),and which contain 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), 1 to 8(i.e. 1, 2, 3, 4, 5, 6, 7 or 8), 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1to 4 (i.e. 1, 2, 3 or 4) carbon atoms, respectively. In a preferredembodiment, —C₁₋₁₀-alkyl, —C₁₋₈-alkyl, —C₁₋₆-alkyl and —C₁₋₄-alkyl aresaturated.

Preferred —C₁₋₁₀-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl,2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl,3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl,3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl,n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH₂CH═CH₂,—CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl,2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl,3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl,2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.Particularly preferred —C₁₋₁₀-alkyl groups are selected from C₁₋₄-alkylgroups.

Preferred —C₁-s-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl,2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl,3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl,3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl,n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH₂CH═CH₂,—CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl,2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl,3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl,2,2-dimethylpropyl, n-hexyl, n-heptyl and n-octyl. Particularlypreferred —C₁₋₈-alkyl groups are selected from C₁₋₄-alkyl groups.

Preferred —C₁₋₆-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl,2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl,2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl,3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferablymethyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂—CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl. Particularly preferred—C₁₋₆-alkyl groups are selected from C₁₋₄-alkyl groups.

Preferred —C₁₋₄-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and3-methylbut-1-ynyl. More preferred —C₁₋₄-alkyl groups are selected frommethyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, andtert-butyl.

Further according to the invention, the terms “—C₁₋₆-alkylene-”;“—C₁₋₄-alkylene-” and “—C₁₋₂-alkylene-” relate to a linear or branched,preferably linear, and preferably saturated aliphatic residues which arepreferably selected from the group consisting of methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂— or —C(CH₃)₂—), butylene(—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—) and hexylene(—CH₂CH₂CH₂CH₂CH₂CH₂—); more preferably methylene (—CH₂—) and ethylene(—CH₂CH₂—) and most preferably methylene (—CH₂—). Preferably,—C₁₋₆-alkylene-is selected from —C₁₋₄-alkylene-, more preferably from—C₁₋₂-alkylene-.

Still further according to the invention, the terms “—C₃₋₁₀-cycloalkyl”and “—C₃₋₆-cycloalkyl” preferably mean cyclic aliphatic hydrocarbonscontaining 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 3, 4, 5 or 6carbon atoms, respectively, wherein the hydrocarbons in each case can besaturated or unsaturated (but not aromatic), unsubstituted or mono- orpolysubstituted.

Preferably, —C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl are saturated. The—C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl can be bound to the respectivesuperordinate general structure via any desired and possible ring memberof the cycloalkyl group. The —C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkylgroups can also be condensed with further saturated, (partially)unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems,i.e. with cycloalkyl, heterocyclyl, aryl or heteroaryl residues, whichin each case can in turn be unsubstituted or mono- or polysubstituted.Further, —C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl can be singly ormultiply bridged such as, for example, in the case of adamantyl,bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. However, preferably,—C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl are neither condensed withfurther ring systems nor bridged. More preferably, —C₃₋₁₀-cycloalkyl and—C₃₋₆-cycloalkyl are neither condensed with further ring systems norbridged and are saturated. Preferred —C₃₋₁₀-cycloalkyl groups areselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, adamantly, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptyl andbicyclo[2.2.2]octyl. Particularly preferred —C₃₋₁₀-cycloalkyl groups areselected from —C₃₋₆-cycloalkyl groups.

Preferred —C₃₋₆-cycloalkyl groups are selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl andcyclohexenyl. Particularly preferred —C₃₋₆-cycloalkyl groups areselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, most preferably cyclopropyl.

According to the invention, the terms “3 to 7-membered heterocycloalkyl”and “3 to 6-membered heterocycloalkyl” preferably meanheterocycloaliphatic saturated or unsaturated (but not aromatic)residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members and 3 to 6,i.e. 3, 4, 5 or 6 ring members, respectively, wherein in each case atleast one, if appropriate also two or three carbon atoms are replaced bya heteroatom or a heteroatom group each selected independently of oneanother from the group consisting of O, S, S(═O), S(═O)₂, N, NH andN(C₁₋₄-alkyl) such as N(CH₃), wherein the carbon atoms of the ring canbe unsubstituted or mono- or polysubstituted. Preferably, the 3 to7-membered heterocycloalkyl and the 3 to 6-membered heterocycloalkylcontain only one heteroatom or heteroatom group within the ring.

Preferably, 3 to 7-membered heterocycloalkyl and 3 to 6-memberedheterocycloalkyl are saturated. The 3 to 7-membered heterocycloalkyl andthe 3 to 6-membered heterocycloalkyl groups can also be condensed withfurther saturated or (partially) unsaturated cycloalkyl or heterocyclyl,aromatic or heteroaromatic ring systems. However, more preferably, 3 to7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are notcondensed with further ring systems. Still more preferably, 3 to7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are notcondensed with further ring systems and are saturated. The 3 to7-membered heterocycloalkyl and the 3 to 6-membered heterocycloalkylgroup can be bound to the superordinate general structure via anydesired and possible ring member of the heterocycloaliphatic residue ifnot indicated otherwise. In a preferred embodiment, 3 to 7-memberedheterocycloalkyl and 3 to 6-membered heterocycloalkyl are bound to thesuperordinate general structure via a carbon atom.

Preferred 3 to 7-membered heterocycloalkyl groups are selected from thegroup consisting of tetrahydrofuranyl, azepanyl, dioxepanyl, oxazepanyl,diazepanyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl,thiomorpholinyl, tetrahydropyranyl, oxetanyl, oxiranyl, morpholinyl,pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl,aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl,dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl,imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl,pyrazolidinyl, pyranyl; tetrahydropyrrolyl, dihydroquinolinyl,dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroindolinyl.Particularly preferred 3 to 7-membered heterocycloalkyl groups areselected from 3 to 6-membered heterocycloalkyl groups.

Preferred 3 to 6-membered heterocycloalkyl groups are selected from thegroup consisting of tetrahydrofuranyl, tetrahydropyranyl, oxetanyl,oxiranyl, thiazolidinyl, tetrahydrothiophenyl, tetra-hydropyridinyl,thiomorpholinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl,morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl,dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl,dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl,tetrahydropyrrolyl, dihydroindolinyl, dihydroisoindolyl andtetrahydroindolinyl. More preferred 3 to 6-membered heterocycloalkylgroups are selected from the group consisting of tetrahydrofuranyl,tetrahydropyranyl, oxetanyl, and oxiranyl; still more preferablytetrahydrofuranyl.

According to the invention, the term “5- to 6-membered heteroaryl”preferably means a 5 or 6-membered cyclic aromatic residue containing atleast 1, if appropriate also 2, 3, 4 or 5 heteroatoms, wherein theheteroatoms are each selected independently of one another from thegroup S, N and O and the heteroaryl residue can be unsubstituted ormono- or polysubstituted, if not indicated otherwise. In the case ofsubstitution on the heteroaryl, the substituents can be the same ordifferent and be in any desired and possible position of the heteroaryl.The binding to the superordinate general structure can be carried outvia any desired and possible ring member of the heteroaryl residue ifnot indicated otherwise. Preferably, the 5- to 6-membered heteroaryl isbound to the suprordinate general structure via a carbon atom of theheterocycle. The heteroaryl can also be part of a bi- or polycyclicsystem having up to 14 ring members, wherein the ring system can beformed with further saturated or (partially) unsaturated cycloalkyl orheterocycloalkyl, aromatic or heteroaromatic ring systems, which can inturn be unsubstituted or mono- or polysubstituted, if not indicatedotherwise. In a preferred embodiment, the 5- to 6-membered heteroaryl ispart of a bi- or polycyclic, preferably bicyclic, system. In anotherpreferred embodiment, the 5- to 6-membered heteroaryl is not part of abi- or polycyclic system.

Preferably, the 5- to 6-membered heteroaryl is selected from the groupconsisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl,oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, pyridone (pyridinone),pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, isothiazolyl,furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl,4,5,6,7-tetrahydro-2H-indazolyl,2,4,5,6-tetrahydrocyclo-penta[c]pyrazolyl, benzofuranyl,benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl,quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl,imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl,naphthyridinyl, oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl,purinyl, phenazinyl, tetrazolyl and triazinyl. Particularly preferred 5-to 6-membered heteroaryl are selected from the group consisting ofpyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl, oxazolyl,isoxazolyl, pyrazolyl, and oxadiazolyl. As pyridones can be regarded aspyridines that are substituted with ═O, for the purpose of thespecification the definition of pyridines that may optionally besubstituted with ═O covers pyridones.

The compounds according to the invention are defined by substituents,for example by R₁, R₂ and R₃ (1^(st) generation substituents) which mayoptionally be for their part themselves be substituted (2^(nd)generation substituents). Depending on the definition, thesesubstituents of the substituents can optionally be for their partresubstituted (3^(rd) generation substituents). If, for example,R₁=phenyl (1^(st) generation substituent), then the phenyl can for itspart be substituted, for example with —C₁₋₆-alkyl (2^(nd) generationsubstituent). This produces the functional group R₁=phenyl-C₁₋₆-alkyl.The —C₁₋₆-alkyl can then for its part be resubstituted, for example with—F (3^(rd) generation substituent). Overall, this produces thefunctional group R₁=phenyl-C₁₋₆-alkyl, wherein the —C₁₋₆-alkyl issubstituted with —F.

However, in a preferred embodiment, the 3^(rd) generation substituentsmay not be resubstituted, i.e. there are then no 4^(th) generationsubstituents. More preferably, the 2^(nd) generation substituents maynot be resubstituted, i.e. there are no 3^(rd) generation substituents.

If a residue occurs multiply within a molecule, then this residue canhave respectively different meanings for various substituents: if, forexample, both R₃ and R_(3′) denote —C₁₋₁₀-alkyl, then —C₁₋₁₀-alkyl cane.g. represent ethyl for R₃ and can represent methyl for R_(3′).

In connection with the terms “—C₁₋₁₀-alkyl”, “—C₁₋₆-alkyl”,“—C₁₋₄-alkyl”, “—C₃₋₁₀-cycloalkyl”, “—C₃₋₆-cycloalkyl”, “3 to 7 memberedheterocycloalkyl”, “3 to 6-membered heterocycloalkyl”,“—C₁₋₆-alkylene-”, “—C₁₋₄-alkylene-” and “—C₁₋₂-alkylene-”, the term“substituted” refers in the sense of the invention, with respect to thecorresponding residues or groups, to the single substitution(monosubstitution) or multiple substitution (polysubstitution), e.g.disubstitution or trisubstitution; more preferably to monosubstitutionor disubstitution; of one or more hydrogen atoms each independently ofone another by at least one substituent. In case of a multiplesubstitution, i.e. in case of polysubstituted residues, such as di- ortrisubstituted residues, these residues may be polysubstituted either ondifferent or on the same atoms, for example trisubstituted on the samecarbon atom, as in the case of —CF₃, —CH₂CF₃ or disubstituted as in thecase of 1,1-difluorocyclohexyl, or at various points, as in the case of—CH(OH)—CH═CH—CHCl₂ or 1-chloro-3-fluorocyclohexyl. The multiplesubstitution can be carried out using the same or using differentsubstituents.

In relation to the terms “phenyl”, “heteroaryl” and “5- to 6-memberedheteroaryl”, the term “substituted” refers in the sense of thisinvention to the single substitution (monosubstitution) or multiplesubstitution (polysubstitution), e.g. disubstitution or trisubstitution,of one or more hydrogen atoms each independently of one another by atleast one substituent. The multiple substitution can be carried outusing the same or using different substituents.

According to the invention, preferably —C₁₋₁₀-alkyl-, —C₁₋₆-alkyl,—C₁₋₄-alkyl, —C₃₋₁₀-cycloalkyl, —C₃₋₆-cycloalkyl, 3 to 7 memberedheterocycloalkyl, 3 to 6-membered heterocycloalkyl, —C₁₋₆-alkylene-,—C₁₋₄-alkylene- and —C₁₋₂-alkylene-in each case independently from oneanother are unsubstituted or mono- or polysubstituted with one or moresubstituents selected from —F; —Cl; —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃;—CF₂H; —CFH₂; —CF₂Cl; —CFCl₂; —C(═O)—C₁₋₆-alkyl; —C(═O)—OH;—C(═O)—OC₁₋₆-alkyl; —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl);—C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂;—O—C₁₋₆-alkyl; —O—C(═O)—C₁₋₆-alkyl; —O—C(═O)—O—C₁₋₆-alkyl;—O—(CO)—NH(C₁₋₆-alkyl); —O—C(═O)—N(C₁₋₆-alkyl)₂; —O—S(═O)₂—NH₂;—O—S(═O)₂—NH(C₁₋₆-alkyl); —O—S(═O)₂—N(C₁₋₆-alkyl)₂; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—NH—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—NH₂; —NH—C(═O)—NH(C₁₋₆-alkyl);—NH—C(═O)—N(C₁₋₆-alkyl)₂; —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-C(═O)—NH₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂OH;—NH—S(═O)₂—C₁₋₆-alkyl; —NH—S(═O)₂—O—C₁₋₆-alkyl; —NH—S(═O)₂—NH₂;—NH—S(═O)₂—NH(C₁₋₆-alkyl); —NH—S(═O)₂N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-S(═O)₂—OH; —N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-S(═O)₂—NH₂;—N(C₁₋₆-alkyl)-S(═O)₂—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂;—S-C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—OH;—S(═O)₂—O—C₁₋₆-alkyl; —S(═O)₂—NH₂; —S(═O)₂—NH(C₁₋₆-alkyl);—S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl; 5 or 6-membered heteroaryl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —O-phenyl;—O-(5 or 6-membered heteroaryl); —C(═O)—C₃₋₆-cycloalkyl; C(═O)-(3 to6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5 or 6-memberedheteroaryl); —S(═O)₂—(C₃₋₆-cycloalkyl); —S(═O)₂-(3 to 6-memberedheterocycloalkyl); —S(═O)₂-phenyl and —S(═O)₂-(5 or 6-memberedheteroaryl).

Preferred substituents of —C₁₋₁₀-alkyl, —C₁₋₆-alkyl, —C₁₋₄-alkyl,—C₃₋₁₀-cycloalkyl, —C₃₋₆-cycloalkyl, 3 to 7 membered heterocycloalkyl, 3to 6-membered heterocycloalkyl, —C₁₋₆-alkylene- and —C₁₋₄-alkylene-areselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl);—C(═O)—N(C₁₋₆-alkyl)₂; —OH; —OCF₃; —OCF₂H; —OCFH₂; —O—C₁₋₆-alkyl; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂; —S-C₁₋₆-alkyl;—S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl and 5 or 6-membered heteroaryl; andparticularly preferably —F, —CN, —CH₃, —CH₂CH₃, —CF₃; —CF₂H; —CFH₂;—C(═O)—NH₂; —C(═O)—NH(CH₃); —C(═O)—N(CH₃)₂; —OH, —NH₂, —OCH₃, —SCH₃,—S(═O)₂(CH₃), —S(═O)(CH₃), —N(CH₃)₂, cyclopropyl and oxetanyl. Accordingto this embodiment, —C₁₋₁₀-alkyl, —C₁₋₆-alkyl, —C₁₋₄-alkyl,—C₃₋₁₀-cycloalkyl, —C₃₋₆-cycloalkyl, 3 to 7 membered heterocycloalkyl, 3to 6-membered heterocycloalkyl are preferably each independently fromone another unsubstituted, mono-di- or trisubstituted, more preferablyunsubstituted or monosubstituted or disubstituted with a substituentselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl);—C(═O)—N(C₁₋₆-alkyl)₂; —OH; —OCF₃; —OCF₂H; —OCFH₂; —O—C₁₋₆-alkyl; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂; —S—C₁₋₆-alkyl;—S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl and 5 or 6-membered heteroaryl; more preferably—F; —Cl; —Br; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —OH; —OCF₃; —OCF₂H;and —OCFH₂; and particularly preferably —F; —Cl; —Br. Preferably,—C₁₋₆-alkylene-groups and —C₁₋₄-alkylene-groups are unsubstituted.

According to the invention, preferably phenyl and 5 or 6-memberedheteroaryl in each case independently from one another are unsubstitutedor mono- or polysubstituted; preferably unsubstituted, mono- di- ortrisubstituted, still more preferably unsubstituted or monosubstitutedor disubstituted; with one or more substituents selected from —F; —Cl;—Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;—C₁₋₄-alkylene-CF₃; C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂;—C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH(OH);—C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; ═O; —OH;—OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —NH—C(═O)—NH₂;—NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂—C₁₋₆-alkyl; —SCF₃;—S-C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—NH₂;—S(═O)₂—NH(C₁₋₆-alkyl); —S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl;—C₁₋₄-alkylene-C₃₋₆-cycloalkyl; 3 to 6-membered heterocycloalkyl;—C₁₋₄-alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or6-membered heteroaryl.

Preferred substituents of phenyl and 5 or 6-membered heteroaryl areselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C₁₋₄-alkylene-CF₃;—C₁₋₄-alkylene-—CF₂H; —C₁₋₄-alkylene-CFH₂; —OH; —OCF₃; —OCF₂H; —OCFH₂;—O—C₁₋₆-alkyl; —O—C₃₋₆-cycloalkyl and —C₃₋₆-cycloalkyl; and morepreferably of —F; —C₁; —Br; —CN; —CH₃; —CH₂CH₃; —CF₃; —CF₂H; —CFH₂;—CH₂—CF₃; ═O; —OH; —OCF₃; —OCF₂H; —OCFH₂; —O—CH₃; —O-cyclopropyl andcyclopropyl; still more preferably —F; —Cl; —Br; —CH₃; —CH₂CH₃; —CF₃;—CF₂H; —CFH₂; ═O; —OH; —OCF₃; and —O—CH₃; and particularly preferablypreferably —F; —Cl; —Br; —CH₃; ═O; and —O—CH₃. According to thisembodiment, phenyl and 5 or 6-membered heteroaryl are preferably eachindependently from one another unsubstituted, mono- di- ortrisubstituted, more preferably unsubstituted or monosubstituted ordisubstituted with a substituent selected from the group consisting of—F; —Cl; —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂;—C₁₋₄-alkylene-CF₃; —C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂; ═O; —OH;—OCF₃; —OCF₂H; —OCFH₂; —O—C₁₋₆-alkyl; —O—C₃₋₆-cycloalkyl and—C₃₋₆-cycloalkyl. A particularly preferred substituted 5 or 6-memberedheteroaryl is N-methyl-2-oxo-pyridyl.

In a preferred embodiment, the compound according to the invention has astereochemistry according to general formula (II), (III), (IV), (V),(VI), (VII), (VIII), or (IX)

In a preferred embodiment, the compound according to the invention has astereochemistry according to general formula (II), (III), (VI) or (VII),such that the residues —R₁ and —NH—R₂ on the pyrrolidone ring areoriented trans. Preferably, the compound according to the invention hasa stereochemistry according to general formula (II) or (VI). Preferably,the compound according to the invention has a stereochemistry accordingto general formula (III) or (VII). The stereochemistry according togeneral formula (II) or (VI) is particularly preferred.

In another preferred embodiment, the compound according to the inventionhas a stereochemistry according to general formula (IV), (V), (VIII) or(IX), such that the residues —R₁ and —NH—R₂ on the pyrrolidone ring areoriented cis. Preferably, the compound according to the invention has astereochemistry according to general formula (IV) or (VIII). Preferably,the compound according to the invention has a stereochemistry accordingto general formula (V) or (IX).

In a particularly preferred embodiment, the compound according to theinvention has a stereochemistry according to general formula (II) or(VI), more preferably (II).

In the compound of the invention according to any of general formulas(I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R₁ representsphenyl; —C₁₋₆-alkylene-phenyl; 5 or 6-memberedheteroaryl;—C₁₋₆-alkylene-(5 or 6-membered heteroaryl); or —C₁₋₁₀-alkyl.

In a preferred embodiment, R₁ represents phenyl or ethyl; morepreferably phenyl.

In a particularly preferred embodiment, R₁ represents phenyl,unsubstituted or mono- or disubstituted with substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br,—OCH₃; —CH₃, —CF₃, —CN, and cyclopropyl; more preferably —F, —OCH₃; and—CH₃.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R_(1′)represents H; —C₁₋₁₀-alkyl; or —C₃₋₁₀-cycloalkyl.

In a preferred embodiment, R_(1′) represents H; methyl, ethyl, n-propyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably H,methyl, ethyl, cyclopropyl or cyclobutyl; still more preferably H,methyl or cyclopropyl.

In a particularly preferred embodiment, R_(1′) represents H.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R₂ represents—C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;—C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-(3 to 7 memberedheterocycloalkyl); —C(═O)—C₁₋₆-alkylene-(3 to 7 memberedheterocycloalkyl); —C(═O)-phenyl; —C(═O)—C₁₋₆-alkylene-phenyl; —C(═O)-(5or 6-membered heteroaryl); —C(═O)—C₁₋₆-alkylene-(5 or 6-memberedheteroaryl); —S(═O)₁₋₂—C₁₋₁₀-alkyl; —S(═O)₁₋₂—C₃₋₁₀-cycloalkyl;—S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂-(3 to 7 memberedheterocycloalkyl); —S(═O)₁₋₂—C₁₋₆-alkylene-(3 to 7 memberedheterocycloalkyl); —S(═O)₁₋₂-phenyl; —S(═O)₁₋₂—C₁₋₆-alkylene-phenyl;—S(═O)₁₋₂-(5 or 6-membered heteroaryl); or —S(═O)₁₋₂—C₁₋₆-alkylene-(5 or6-membered heteroaryl).

In a preferred embodiment, R₂ represents —C(═O)—C₁₋₁₀-alkyl;—C(═O)—C₃₋₁₀-cycloalkyl; —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)-(5 or 6-memberedheteroaryl); —S(═O)₂—C₁₋₁₀-alkyl; —S(═O)₂—C₃₋₁₀-cycloalkyl;—S(═O)₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₂-(3 to 7 memberedheterocycloalkyl); or —S(═O)₂-(5 or 6-membered heteroaryl).

In particularly preferred embodiments, R₂ represents

-   (i) —C(═O)—C₁₋₁₀-alkyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, and —Br;-   (ii) —C(═O)-cyclopropyl, unsubstituted or mono- or disubstituted    with substituents independently of one another selected from the    group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃;-   (iii) —C(═O)-2-tetrahydrofuranyl, unsubstituted;-   (iv) —C(═O)-(5- to 6-membered heteroaryl), wherein said 5- to    6-membered heteroaryl is selected from the group consisting of    thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl,    1,2,5-oxadiazolyl, and isothiazolyl, wherein in each case said 5- to    6-membered heteroaryl is unsubstituted or mono- or disubstituted    with substituents independently of one another selected from the    group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, ═O, and —OCH₃;-   (v) —S(═O)₂—C₁₋₁₀-alkyl, unsubstituted;-   (vi) —S(═O)₂-cyclopropyl, unsubstituted;-   (vii) —S(═O)₂—CH₂-cyclopropyl, unsubstituted;-   (viii) —S(═O)₂-2-tetrahydrofuranyl; or-   (ix) —S(═O)₂-(5- to 6-membered heteroaryl), wherein said 5- to    6-membered heteroaryl is selected from the group consisting of    thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl,    1,2,5-oxadiazolyl, and isothiazolyl, wherein in each case said 5- to    6-membered heteroaryl is unsubstituted or mono- or disubstituted    with substituents independently of one another selected from the    group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, ═O, and —OCH₃.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R₃ and R_(3′)independently from one another represent H; F; Cl; —C₁₋₁₀-alkyl;—C₃₋₆-cycloalkyl; —CH₂—C₃₋₆-cycloalkyl; 3 to 7 memberedheterocycloalkyl; —CH₂-(3 to 7 membered heterocycloalkyl); —CH₂-phenyl;or —CH₂-(5 or 6-membered heteroaryl); or R₃ and R_(3′) together with thecarbon atom to which they are bound form a C₃₋₁₀-cycloalkyl, or 3 to 7membered heterocycloalkyl.

In a preferred embodiment, R₃ and R_(3′) both represent —C₁₋₁₀-alkyl. Ina particularly preferred embodiment, R₃ and R_(3′) both represent —CH₃.

In another preferred embodiment, R₃ and R_(3′) independently from oneanother represent H; F; —CH₃; cyclopropyl; —CH₂-cyclopropyl; or—CH₂-phenyl. In still another preferred embodiment, R₃ and R_(3′) bothrepresent F.

In another preferred embodiment, at least one of R₃ and R_(3′)represents not H. In yet another preferred embodiment, one of R₃ andR_(3′) represents H.

In still another preferred embodiment, R₃ and R_(3′) together with thecarbon atom to which they are bound form cyclopropyl.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R₄ representsphenyl; —C₁₋₆-alkylene-phenyl; 5 or 6-membered heteroaryl; or—C₁₋₆-alkylene-(5 or 6-membered heteroaryl).

In a preferred embodiment, R₄ represents phenyl or 5 or 6-memberedheteroaryl.

In particularly preferred embodiments, R₄ represents phenyl,unsubstituted or mono- or disubstituted with substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br, —CH₃,—CF₃, —CN, and —OCH₃; or 5 or 6-membered heteroaryl selected from thegroup consisting of pyridyl, pyrazolyl, and pyrimidinyl, wherein in eachcase said 5- to 6-membered heteroaryl is unsubstituted or mono- ordisubstituted with substituents independently of one another selectedfrom the group consisting of ═O, —F, —Cl, —Br, —CH₃, —CF₃, —CN, and—OCH₃.

In a particularly preferred embodiment, R₄ does not representN-methylpyridinone.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) A, X, Y and Zindependently from one another represent N or CH. In a preferredembodiment, A represents N.

In a preferred embodiment, X represents CH.

In a preferred embodiment, Y represents CH.

In a preferred embodiment, Z represents CH.

In a preferred embodiment of the invention,

-   (i) A represents N, X represents CH, Y represents CH; and Z    represents CH; or-   (ii) A represents N, X represents N, Y represents CH; and Z    represents CH; or-   (iii) A represents N, X represents CH, Y represents N; and Z    represents CH; or-   (iv) A represents N, X represents CH, Y represents CH; and Z    represents N; or-   (v) A represents N, X represents N, Y represents N; and Z represents    CH; or-   (vi) A represents N, X represents N, Y represents CH; and Z    represents N; or-   (vii) A represents N, X represents CH, Y represents N; and Z    represents N; or-   (viii) A represents N, X represents N, Y represents N; and Z    represents N; or-   (ix) A represents CH, X represents CH, Y represents CH; and Z    represents CH; or-   (x) A represents CH, X represents N, Y represents CH; and Z    represents CH; or-   (xi) A represents CH, X represents CH, Y represents N; and Z    represents CH; or-   (xii) A represents CH, X represents CH, Y represents CH; and Z    represents N; or-   (xiii) A represents CH, X represents N, Y represents N; and Z    represents CH; or-   (xiv) A represents CH, X represents N, Y represents CH; and Z    represents N; or-   (xv) A represents CH, X represents CH, Y represents N; and Z    represents N; or-   (xvi) A represents CH, X represents N, Y represents N; and Z    represents N.

In a particularly preferred embodiment of the invention according to anyof general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or(IX)

-   -   R₁ represents phenyl, unsubstituted or mono- or disubstituted        with substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —CH₃, and —OCH₃; and/or    -   R_(1′) represents H, CH₃, or cyclopropyl and/or    -   R₂ represents —C(═O)—C₁₋₆-alkyl; —C(═O)-cyclopropyl; or or        —C(═O)-(5- to 6-membered heteroaryl), unsusbtituted or mono- or        disubstituted with substituents independently of one another        selected from the group consisting of —F, —Cl, —Br; and —CH₃;        and/or    -   R₄ represents fluoro-phenyl or N-methyl-2-oxo-pyridyl.

In a preferred embodiment, the compound according to the invention isselected from the group consisting of

-   1    N-[(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   2    N-[(2S,3R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   3    N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic    acid amide-   4    2,2-Difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide-   5    N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic    acid amide-   6    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carboxylic    acid amide-   7    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylic    acid amide-   8    N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   9    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   10    2,2-Difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide-   12    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide-   13    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylic    acid amide-   14    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxylic    acid amide-   15    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylic    acid amide-   16    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   17    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic    acid amide-   18    N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylic    acid amide-   21    N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylic    acid amide-   22    N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylic    acid amide-   24    N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylic    acid amide-   26    N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carboxylic    acid amide-   30    N-[rac-(6R,7S)-5-[1-(1-Methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic    acid amide-   31    N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic    acid amide-   32    N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic    acid amide-   33    N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylic    acid amide-   34a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)methanesulfonamide-   34b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)methanesulfonamide-   35a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanesulfonamide-   35b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanesulfonamide-   36a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)oxazole-5-carboxamide-   36b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)oxazole-5-carboxamide-   37    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide-   38a    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide-   38b    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide-   39a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide-   39b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide-   40a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide-   40b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide-   41a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide-   41b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide-   42a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)nicotinamide-   42b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)nicotinamide-   43a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)pyrimidine-2-carboxamide-   43b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)pyrimidine-2-carboxamide-   44a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide-   44b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide-   45a    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide-   45b    N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide-   46    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   47    N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   48    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(3-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   49    N-[rac-(2R,3S,4S)-2-(4-Fluorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   60    N-[rac(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   61    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-methanesulfonic    acid amide-   62    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   63    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   64    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-i    H-pyrazole-3-carboxylic acid amide-   65    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   66    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   67    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   68    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   69    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   70    N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   71    N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   72    N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-1-methyl-i    H-pyrazole-3-carboxylic acid amide-   73    N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   74    N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   75    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-1-methyl-i    H-pyrazole-3-carboxylic acid amide-   76    N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   77    2,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide-   78    N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   79    N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   80    2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide-   81    2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide-   82    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   83    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide-   84    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   85    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   86    N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   87    N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   88    N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   89    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   90    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   91    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   92    N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   93    N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   94    N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide-   95    N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   96    N-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   97    2,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide-   98    2,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide-   99    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   100    2,2-Difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide-   101    N-[rac-(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   102    2,2-Difluoro-N-[rac-(2R,3S)-2-methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide-   103    N-[rac-(2R,3S)-2-Methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   104    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide-   105    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   106    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   107    N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   108    N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   109    N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   110    N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide-   111    N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   112    N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   113    N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   114    N-[(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   115    N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   116    N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic    acid amide-   117    N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide-   118    N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylic    acid amide-   119    N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic    acid amide-   120    2,2-Difluoro-N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-propionamide-   121    N-[rac-(2R,3S,4S)-4-(Cyclopropyl-methyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   122    N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-methanesulfonic    acid amide-   123    N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   124    N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   125    N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide-   126    N-[rac-(2R,3S,4S)-4-Ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   127    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide,    diastereomer 2-   128    N-[rac-(2R,3R,4R)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   129    N-[rac-(2R,3R,4S)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   130    N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide,    diastereomer 1-   131    N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   132    N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   133    N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic    acid amide-   134    N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   135    N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspiro[3.4]octan-8-yl)cyclopropanecarboxamid-   136 N-(rac    (2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   137    N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide-   138    N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   139    N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanec    arboxamide-   142    N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   143    N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   144    N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide-   145    N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide-   146    N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide-   147    N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide-   148    N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   149    N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide-   150    N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(thiazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide-   151    N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide    in each case in the form of the free compound or a physiologically    acceptable salt thereof.

The compounds according to the invention can be synthesized by standardreactions in the field of organic chemistry known to the person skilledin the art or in a manner as described herein (cf. Reaction Schemesbelow) or analogously. The reaction conditions in the synthesis routesdescribed herein are known to the skilled person and are for some casesalso exemplified in the Examples described herein.

Reaction Scheme 1:

Substituted indazole moieties in compounds of formula (D) and formula(F) are introduced by subjecting lactam (B) or lactam (E) in aregioselective metal catalyzed C—N coupling reaction with correspondingindazole halides (C), preferred with corresponding indazole iodides.Metal catalyzed C—N coupling reactions are generally known in the art(Current Organic Synthesis, 2011, 8, 53). Favorable C—N couplingreactions are palladium and copper catalyzed cross-coupling reactions(Chem. Rev., 2016, 116, 12564; Chem. Soc. Rev., 2014, 43, 3525; Chem.Sci., 2010, 1, 13). Regioselective C—N couplings with arylhalides areknown in the art (Chem. Sci., 2011, 2, 27; J. Am. Chem. Soc., 2001, 123,7727).

Primary amines (A) and (G) are converted to corresponding amides andsulfonamides (acylation and sulfonamide formation) (B) and (D) usingcommercially available acids (activation of acids using e.g. HATU) oracid chlorides under standard amide coupling reaction conditions(March's Advanced Organic Chemistry, 2007, 6th Edition, page 1427-1474).

Introduction of different orthogonal protecting groups PG (e.g. Boc,Cbz) to convert (A) to (E) as well as deprotection of compounds offormula (E) to (A) is well described in the literature (T. W. Green, P.G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience,New York, 1999).

Reaction Scheme 1.1:

Compounds (A) and (E) can be synthesized according to procedures whichare described in the literature.

Route 1:

Synthesis of compounds of formula (I) starting from compounds of formula(H) is described in the literature (Org. Lett., 2011, 13, 6406, Org.Lett, 2009, 4512, ACS Sustainable Chem. Eng. 2015, 1873). For R₃ andR_(3′)=Me the synthesis of the corresponding acid of (H) is described(Journal of Chemical and Engineering Data, 1966, 11, 617) and thesynthesis can be carried out in analogy to the references above. Removalof PG=PMB is well known in the art (Greene's Protective Groups inOrganic Synthesis, 2007, 4th Edition, page 905ff). Reduction of nitrogroups is well known in the art (March's Advanced Organic Chemistry,2007, 6th Edition, page 1815f).

Route 2:

Synthesis of compounds of formula (J) is described in the literature(Org. Lett., 2007, 9, 4077). Introduction of substituents R3 and R3′ canbe achieved via alkylation. C-alkylations of pyrrolidinones(Tetrahedron, 1999, 55, 13321) and elimination of sulfonium salts(Tetrahedron Letters 1983, 24, 4331) are well known in the art.Compounds of formula (A) and (E) can be synthesized using Curtiusrearrangement as key step to convert carboxylic acid (L) tocorresponding primary amine (A) or (E). Curtius rearrangement is wellknown in the art (Tetrahedron Letters, 2010, 51, 385).

Route 3:

Synthesis of compounds of formula (N) starting from compounds of formula(M) is described in the literature (J. Am. Chem. Soc., 2008, 130,16146). Amidophosphate cleavage is described in the literature (J. Am.Chem. Soc., 2008, 130, 16146). Compounds of formula (A) and (E) can besynthesized using Curtius rearrangement as key step to convertcarboxylic acid (L) to corresponding primary amine (A) or (E). Curtiusrearrangement is well known in the art (Tetrahedron Letters, 2010, 51,385).

Reaction Scheme 2:

Compounds of formula (D) can be synthesized via regioselective C—Ncoupling of compound (O). Suitable C—N coupling reactions for N—Hcontaining heterocycles are known in the art (Synthesis, 2011, 829;Chem. Sci., 2011, 2, 27; Beilstein J. Org. Chem., 2011, 7, 59; J. Org.Chem., 2004, 69, 5578). Compound of formula (O) is synthesized viadeprotection of compound (N) under acidic conditions.

The compounds according to the invention can be produced in the mannerdescribed here or in an analogous manner.

In a preferred embodiment, the compounds according to the invention aremodulators of the glucocorticoid receptor. In the sense of theinvention, the term “selective modulator of the glucocorticoid receptor(glucocorticoid receptor modulator)” preferably means that therespective compound exhibits in a cellular target engagement assay foragonistic or antagonistic potency on the glucocorticoid receptor an EC50or IC50 value on the glucocorticoid receptor of at most 15 μM (10·10⁻⁶mol/L) or at most 10 μM; more preferably at most 1 μM; still morepreferably at most 500 nM (10⁻⁹ mol/L); yet more preferably at most 300nM; even more preferably at most 100 nM; most preferably at most 10 nM;and in particular at most 1 nM. In a preferred embodiment, the compoundaccording to the invention exhibits in a cellular target engagementassay for agonistic or antagonistic potency on the glucocorticoidreceptor an EC50 or IC50 value on the glucocorticoid receptor in therange of from 1 μM to 15 μM, more preferably from 100 nM to 1 μM, mostpreferably below 100 nM.

The person skilled in the art knows how to test compounds for modulation(agonistic or antagonistic) of the activity of the glucocorticoidreceptor. Preferred target engagement assays for testing compounds fortheir agonistic or antagonistic potency (EC50, IC50) on theglucocorticoid receptor are described herein below:

Glucocorticoid Receptor Cell-Based Assays

Potential selective glucocorticoid receptor modulators of thisintervention can be tested for modulation of the activity of theglucocorticoid receptor using cell-based assays. These assays involve aChinese hamster ovary (CHO) cell line which contains fragments of theglucocorticoid receptor as well as fusion proteins. The glucocorticoidreceptor fragments used are capable of binding the ligand (e.g.beclomethasone) to identify molecules that compete for binding withglucocorticoid receptor ligands. In more detail, the glucocorticoidreceptor ligand binding domain is fused to the DNA binding domain (DBD)of the transcriptionfactor GAL4 (GAL4 DBD-GR) and is stably integratedinto a CHO cell line containing a GAL4-UAS-Luciferase reporterconstruct. To identify selective glucocorticoid receptor modulators, thereporter cell line is incubated with the molecules using an 8-pointhalf-log compound dilution curve for several hours. After cell lysis theluminescence that is produced by luciferase after addition of thesubstrate is detected and EC50 or IC50 values can be calcuated.Engagement of molecules which induce gene expression via glucocortocoidreceptor binding to the DNA leads to expression of the luciferase geneunder the control of the fusion protein GAL4 DBD-GR and therefore to adose-dependent increase of the luminescence signal. Binding of moleculeswhich repress beclomethasone-induced gene expression of the luciferasegene under the control of the fusion protein GAL4 DBD-GR leads to adose-dependent reduction of the luminescence signal.

In a preferred embodiment, the compound according to the inventionexhibits in a cellular target engagement assay for agonistic orantagonistic potency on the glucocorticoid receptor an EC50 or IC50value on the glucocorticoid receptor of at most 1 μM (10⁻⁶ mol/L); stillmore preferably at most 500 nM (10⁻⁹ mol/L); yet more preferably at most300 nM; even more preferably at most 100 nM; most preferably at most 50nM; and in particular at most 10 nM or at most 1 nM.

In a preferred embodiment, the compound according to the inventionexhibits in a cellular target engagement assay for agonistic orantagonistic potency on the glucocorticoid receptor an EC50 or IC50value on the glucocorticoid receptor in the range of from 1 μM to 15 μM,more preferably from 100 nM to 1 μM, most preferably below 100 nM.

In a preferred embodiment, the compound according to the inventionexhibits in a cellular target engagement assay for agonistic orantagonistic potency on the glucocorticoid receptor an EC50 or IC50value on the glucocorticoid receptor in the range of from 0.1 nM (10⁻⁹mol/L) to 1000 nM; still more preferably 1 nM to 800 nM; yet morepreferably 1 nM to 500 nM; even more preferably 1 nM to 300 nM; mostpreferably 1 nM to 100 nM; and in particular 1 nM to 80 nM.

Human Glucocorticoid Receptor (hGR) Ligand-Binding Assay

Potential selective glucocorticoid receptor modulators of thisintervention can be tested for their binding affinity at theglucocorticoid receptor using the binding assay described below.

Preferably, the glucocortitcoid receptor extracted from cytosol of IM9cells is used for competitive radioligand binding assays to calculatepercentage inhibition of the binding of radiolabeled ligand3H-dexamethasone at the human glucocorticoid receptor. Preferably, afixed concentration of the radioligand 3H-dexamethasone and 1 μM ofcompound according to the present invention (as unlabeled competitors ofdexamethasone) are mixed with the extracted glucocorticoid receptor inorder to measure the percentage of inhibition of 3H-dexamethasonebinding.

In a preferred embodiment, the compound according to the inventionexhibits in a hGR ligand-binding assay an inhibition of 3H-dexamethasonebinding at 1 μM of at least 40%, more preferably at least 60%, mostpreferably at least 85%. In a preferred embodiment, the compoundaccording to the invention exhibits in a hGR ligand-binding assay aninhibition of 3H-dexamethasone binding at 1 μM which is in the rangefrom 40% to 60%, more preferably from greater than 60% to 85%, mostpreferably greater than 85%.

Preferably, the compounds according to the invention are useful asselective modulators of the glucocorticoid receptor.

Therefore, the compounds according to the invention are preferablyuseful for the in vivo treatment or prevention of diseases in whichparticipation of the glucocorticoid receptor is implicated.

The invention therefore further relates to a compound according to theinvention for use in the modulation of glucocorticoid receptor activity.

Therefore, another aspect of the invention relates to a compoundaccording to the invention for use in the treatment and/or prophylaxisof a disorder which is mediated at least in part by the glucocorticoidreceptor. Still another aspect of the invention relates to a method oftreatment of a disorder which is mediated at least in part by theglucocorticoid receptor comprising the administration of atherapeutically effective amount of a compound according to theinvention to a subject in need thereof, preferably a human.

A further aspect of the invention relates to the use of a compoundaccording to the invention as medicament.

Another aspect of the invention relates to a pharmaceutical dosage formcomprising a compound according to the invention. Preferably, thepharmaceutical dosage form comprises a compound according to theinvention and one or more pharmaceutical excipients such asphysiologically acceptable carriers, additives and/or auxiliarysubstances; and optionally one or more further pharmacologically activeingredient. Examples of suitable physiologically acceptable carriers,additives and/or auxiliary substances are fillers, solvents, diluents,colorings and/or binders. These substances are known to the personskilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe furPharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical dosage form according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration. Therefore, the pharmaceutical dosage form can be in formof a liquid, semisolid or solid, e.g. in the form of injectionsolutions, drops, juices, syrups, sprays, suspensions, tablets, patches,films, capsules, plasters, suppositories, ointments, creams, lotions,gels, emulsions, aerosols or in multiparticulate form, for example inthe form of pellets or granules, if appropriate pressed into tablets,decanted in capsules or suspended in a liquid, and can also beadministered as such.

The pharmaceutical dosage form according to the invention is preferablyprepared with the aid of conventional means, devices, methods andprocesses known in the art. The amount of the compound according to theinvention to be administered to the patient may vary and is e.g.dependent on the patient's weight or age and also on the type ofadministration, the indication and the severity of the disorder.Preferably 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, mostpreferably 0.05 to 50 mg of a compound according to the invention areadministered per kg of the patient's body weight.

The glucocorticoid receptor is believed to have potential to modify avariety of diseases or disorders in mammals such as humans. Theseinclude in particular inflammatory diseases.

Another aspect of the invention relates to a compound according to theinvention for use in the treatment and/or prophylaxis of pain and/orinflammation; more preferably inflammatory pain.

A further aspect of the invention relates to a method of treatment ofpain and/or inflammation; more preferably inflammatory pain.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

The following abbreviations are used in the descriptions of theexperiments: AcOH=acetic acid; Cbz=carboxybenzyl; DCM=dichloromethane;DEA=diethylamine; DIPEA=N,N-diisopropylethylamine;DMAP=4-(dimethylamino)-pyridine; DMF=N,N-dimethylformamide;DMSO=dimethylsulfoxide; DPPA=diphenyl phosphoryl azide; EtOAc=ethylacetate; EtOH=ethanol;HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate; h=hour; MeOH=methanol; min=minute;sat.=saturated; RT=room temperature; R_(t)=retention time;tert=tertiary; TEA=triethylamine; TFA=trifluoro acetic acid;THF=tetrahydrofuran.

Synthesis of trans-benzyl4,4-dimethyl-(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (intermediate A1)

Step 1:

A solution of benzaldehyde (95.18 g, 0.898 mol), 4-methylbenzenethiol(111.37 g, 0.898 mol), maleic anhydride (88.04 g, 0.898 mol) and2,4-dimethoxybenzylamine (150.00 g, 0.898 mol) in toluene (600 ml) wasstirred at ambient temperature for 2 h and was then heated to 120° C.for 16 h. After completion of the reaction (monitored by TLC, mobilephase 5% MeOH-DCM, Rf 0.4) the reaction mixture was cooled to ambienttemperature and was concentrated under reduced pressure to obtain thecrude product which was triturated with MTBE to afford1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid (150.0 g, 35%) as an off white solid.

Step 2:

To a suspension of1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid (500.0 g, 1.05 mol) in acetone (5 L) was added K₂CO₃ (579.0 g, 4.19mol) followed by methyl iodide (261.0 ml, 4.19 mol). The resultingsuspension was stirred at ambient temperature for 16 h. The reactionmixture was then filtered and the filtrate was concentrated. The residuewas taken up in EtOAc (1.5 L) and was washed with water. The organiclayer was washed with brine, dried over sodium sulfate and wasconcentrated under reduced pressure to afford1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid methyl ester (480.0 g, 94%) as an off white solid.

Step 3:

To a solution of1-(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid methyl ester (50.0 g, 0.101 mol) in DMF (0.5 L) was added sodiumhydride (50% in mineral oil, 24.4 g, 0.509 mol) at 0° C. The resultingreaction mixture was stirred at 0° C. for 30 minutes. After 30 minutes,methyl iodide (31.7 ml, 0.509 mol) was added slowly. The resultingreaction mixture was then stirred for 30 min at 0° C. After completionof the reaction (monitored by TLC, mobile phase 30%-ethylacetate-hexane, Rf 0.3) the reaction was quenched with saturatedammonium chloride solution and extracted with EtOAc (2.0 L). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure to obtain the crude compound, which was purifiedby column chromatography (silica gel, 100-200 mesh, 10-20% EtOAc/hexane)to afford1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylicacid methyl ester (28.0 g, 70%) as a pale yellow solid.

Step 4.

To a solution of1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylicacid methyl ester (26.0 g, 0.117 mol) in methanol (300 ml) was added 10%palladium on charcoal (50% moisture, 13.4 g, 0.063 mol) and theresulting mixture was stirred for 16 h at ambient temperature underhydrogen pressure (balloon pressure). After completion of the reaction(monitored by TLC, mobile phase 30%-ethyl acetate-hexane, R_(f) 0.30)the reaction mixture was filtered through a celite pad. The filtrate wasconcentrated under reduced pressure to obtain the crude compound whichwas triturated in diethyl ether to afford1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylicacid methyl ester (25.0 g, 96%).

Step 5:

A stirred suspension of1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylicacid methyl ester (25.0 g, 0.063 mol) in TFA (250 ml) was heated to 90°C. for 16 h. After completion of the reaction (monitored by TLC, 50%ethyl ether-hexane, R_(f)-0.3) the reaction was cooled to ambienttemperature and was concentrated under reduced pressure. The remainswere basified with sat. NaHCO₃ solution, followed by the addition ofEtOAc (1 L) and stirring of the resulting mixture for 30 minutes. Theobtained solid was filtered off and dried under high vacuum to afford4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid methyl ester(18.0 g, crude) which was used in the next step.

Step 6.

To a suspension of 4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylicacid methyl ester (43.0 g, 0.174 mmol) in MeOH (400 ml) was added 2 MNaOH (174 ml) at 0° C. The resulting suspension was stirred at 100° C.for 4 h. After consumption of the starting material (monitored by TLC,mobile phase 5% MeOH/DCM, Rf 0.2) the reaction mixture was concentratedand the residue was diluted with water and was washed with ethyl acetate(2×75 ml). The aqueous layer was then acidified to pH 3 with 6N HCl andwas extracted with 10% MeOH/DCM (2×75 ml). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to affordtrans-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid (22.0 g,55.0%) as a brown solid.

Step 7.

To a stirred solution oftrans-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidine-3-carboxylic acid (22.0 g,0.095 mol) in benzene-THF (4:1, 125 ml) was added DPPA (25.0 ml, 0.114mol) followed by TEA (13.35 ml, 0.095 mol) at ambient temperature andthe mixture was stirred for 2 h. Benzyl alcohol (14.8 ml, 0.142 mol) wasthen added and the reaction mixture was heated to 90° C. for 4 h. Aftercompletion of the reaction (monitored by TLC) the reaction mixtire wasdiluted with water (10 ml) and extracted with ethyl acetate (3×100 ml).The combined organic layers were washed with 10% citric acid solution(100 ml) followed by saturated NaHCO₃ solution (2×100 ml) and were thendried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was triturated with diethyl ether (2×80 ml). The obtained solidwas filtered off and was dried under high vacuum to afford intermediateA1 (25.0 g, 78%) as an off white solid.

Synthesis ofN-((trans)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(intermediate A2)

Step 1:

To a stirred solution of intermediate A1 (5.0 g, 14.775 mmol, 1.0 eq.)in methanol:THF (80 mL, 2:1), Pd/C (10.0 g, 10%, moist) was added andthe reaction was stirred under a hydrogen balloon for 2 h at ambienttemperature. After completion, (monitored by TLC, TLC system 5% methanolin DCM, Rf-0.2) the reaction mixture was filtered through a celite padwhich was then washed 2-3 times with THF. The filtrate was concentratedto obtain (trans)-4-amino-3,3-dimethyl-5-phenylpyrrolidin-2-one as abrown gum (3.0 g, 99%).

Step 2:

To a stirred solution of cyclopropanecarboxylic acid (0.253 g, 2.941mmol, 1.2 eq) in DMF (10 mL), HATU (1.86 g, 4.90 mmol, 2.0 eq), DIPEA(2.0 ml 12.25 mmol, 5.0 eq) and(trans)-4-amino-3,3-dimethyl-5-phenylpyrrolidin-2-one (0.50 g, 2.45mmol, 1.0 eq) were added at 0° C. and the reaction was stirred atambient temperature for 16 h. After completion of the reaction(monitored by TLC, TLC system 5% methanol in DCM, Rf-0.3) the reactionmixture was diluted with EtOAc (50 mL), washed with ice cold water (3×25mL), dried over Na₂SO₄ and concentrated to obtain a residue which waspurified via column chromatography (230-400 mesh silica gel; 0 to 2%MeOH-DCM) to afford intermediate A2 (0.46 g, 70%).

Synthesis ofN-((trans)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide(intermediate A3)

Step 1:

To a stirred solution of 2,2-difluoropropanoic acid (0.647 g, 5.88 mmol,1.2 eq) in DMF (15 mL), HATU (3.72 g, 9.80 mmol, 2.0 eq), DIPEA (4.0 ml24.50 mmol, 5.0 eq), and(trans)-4-amino-3,3-dimethyl-5-phenylpyrrolidin-2-one (1.0 g, 4.90 mmol,1.0 eq) were added at 0° C. and the reaction was stirred at ambienttemperature for 16 h. After completion of the reaction (monitored byTLC, TLC system 5% methanol in DCM, Rf-0.3) the reaction mixture wasdiluted with ethyl acetate (50 mL), washed with ice cold water (3×25mL), dried over Na₂SO₄ and concentrated to obtain a residue which waspurified by column chromatography (230-400 mesh silica gel; 0 to 2%MeOH-DCM) to afford intermediate A3 (0.93 g, 64%).

Synthesis of5-(5-((4S,5R)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one(intermediate A4-ent1) and5-(5-((4R,5S)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one(intermediate A4-ent 2)

Step 1:

To a stirred solution of trans-benzyl4,4-dimethyl-(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (2.0 g, 5.91 mmol)in 1,4-dioxane (80 ml) in a sealed tube was added5-(5-iodo-indazol-1-yl)-1-methyl-1H-pyridin-2-one (2.28 g, 6.5 mmol)followed by potassium phosphate (2.51 g, 11.83 mmol). The mixture wasdegassed under argon atmosphere for 30 minutes. Trans-N,N′-dimethylcyclohexane-1,2-diamine (0.37 ml, 2.36 mmol) and CuI (225 mg, 1.18 mmol)were added and the mixture was heated to 90° C. for 16 h. Aftercompletion of the reaction (monitored by LCMS) the reaction mixture wasfiltered through a celite bed and the celite bed was washed with1,4-dioxane (100 ml). The filtrate was then concentrated under reducedpressure. The reaction was carried out in parallel in four batches (2.0g each) and the remains of all batches were purified together by columnchromatography (silica gel, 100-200 mesh, 1-2% MeOH/DCM) to affordbenzyl((trans)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-carbamate(12.8 g, 48%) as a pale yellow solid.

Step 2:

A stirred suspension of benzyl((trans)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-carbamate(3.0 g, 5.35 mmol) in TFA (30 ml) was heated to 90° C. for 3 h. Aftercompletion of the reaction (monitored by LCMS, 5% MeOH in DCM), thereaction mixture was cooled to ambient temperature and was concentratedunder reduced pressure. The remains were then azeotroped with toluene(2×50 ml). The resulting residue was basified with saturated NaHCO₃solution and the mixture was extracted with 5% MeOH/DCM (2×150 ml). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to obtain the crude compound. Thisreaction was conducted in parallel in four batches (3.0 g each) and thecombined crude compound was purified by column chromatography (100-200Silica gel, 1.5-2% MeOH/DCM as eluent) to afford5-(5-((trans)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one(7.0 μg, 76%) as a grey solid.

Chiral separation (Chiralpak IC (21.0×250 mm), 5 μm, mobile phaseDCM:EtOH 50:50, flow rate 18.0 mL/min) of the racemic compound (7.0 g)in normal phase afforded (intermediate A4-ent1, retention time 5.56minutes) and (intermediate A4-ent2, retention time 6.41 minutes).

Synthesis ofN-[rac-((6R,7S)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide(intermediate A5)

Step 1:

To a stirred solution of(2,4-dimethoxy-benzyl)-5-oxo-2-phenyl-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacidmethyl ester (56.0 g 152.42 mmol) in DMF (560 ml) was slowly added NaH(18.3 g, 60% dispersion in mineral oil, 457.24 mmol) followed by1,2-dibromoethane (17.13 ml, 198.14 mmol) at 0° C. The resultingreaction mixture was stirred at 0° C. for 3 h. After completion of thereaction (monitored by TLC, mobile phase 20%-ethyl acetate-hexane, R_(f)0.4) the reaction mixture was poured into a cold saturated solution ofNH₄Cl. The mixture was then extracted with EtOAc (2×1 L). The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure to obtain the crude compound whichwas purified by column chromatography (100-200 mesh silica gel, 10%ethyl acetate-hexane as eluent) to afford methyl5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-azaspiro[2.4]hept-6-ene-7-carboxylate(34.0 g, 57%) as an off-white solid.

Step 2:

To a stirred solution of methyl5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-azaspiro[2.4]hept-6-ene-7-carboxylate(7.5 g, 19.08 mmol) in MeOH (125 ml) was added 10% Pd/C (3.0 g, 50%moist) and a catalytic amount of AcOH. The reaction mixture was stirredunder hydrogen pressure (using a balloon) until consumption of startingmaterial (monitored by LCMS) was achieved. The reaction was carried outin parallel in two batches, which were united for workup. The combinedreaction mixture was filtered through a celite bed, which was washedwith MeOH (75 ml). The filtrate was then concentrated to afford crude5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxylicacid methyl ester (12.0 g), which was used in next step without furtherpurification.

Step 3:

A stirred suspension of5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxylicacid methyl ester (16.0 g, 40.5 mmol) in TFA (80 ml) was heated to 50°C. for 14 h. After completion of the reaction (monitored by LCMS) thereaction mixture was cooled to ambient temperature and was concentratedunder reduced pressure. The remains were azeotroped with toluene, werethen basified with NaHCO₃ solution followed by extraction with ethylacetate (2×125 ml). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford 4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxylic acid methylester (9.0 g crude) as a brown solid.

Step 4:

To a suspension of 4-oxo-6-phenyl-5-aza-spiro[2.4]heptane-7-carboxylicacid methyl ester (9.0 g crude) in MeOH (90 ml) was added 2 M NaOH (60ml, 3.0 eq.) at 10° C. The resulting suspension was then stirred at 100°C. for 4 h. After completion of the reaction (monitored by TLC, mobilephase 50% EtOAc-hexane, R_(f) 0.1) the reaction mixture wasconcentrated. The residue was diluted with water and washed with EtOAc.The basic aqueous layer was acidified to pH 2-3 with 6N HCl and was thenextracted with 10% MeOH/DCM (3×60 ml). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to affordtrans-4-oxo-6-phenyl-5-azaspiro[2.4]heptane-7-carboxylic acid (40 g, 32%over 3 steps) as a brown solid.

Step 5:

To a stirred solution oftrans-4-oxo-6-phenyl-5-azaspiro[2.4]heptane-7-carboxylic acid (5.0 g,21.6 mmol) in benzene-THF (4:1, 80 ml) and DPPA (5.6 ml, 25.9 mmol) wasadded TEA (3 ml, 21.6 mmol) at ambient temperature. The resultingreaction mixture was stirred at ambient temperature for 2 h followed bythe addition of benzyl alcohol (3.4 ml, 32.4 mmol) and heating to 90° C.for 4 h. After completion of the reaction (monitored by TLC, mobilephase 5% MeOH in DCM, R_(f)0.4) the reaction mixture was diluted withwater and extracted with ethyl acetate (3×20 ml). The combined organiclayers were washed with a 10% citric acid solution, then sat. NaHCO₃,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was triturated with 10% DCM-Hexane followed by MTBE (25ml). The obtained solid was filtered off and dried to afford 6.5 g ofthe crude compound, which was purified by prep HPLC to affordN-(trans-4-oxo-6-phenyl-5-aza-spiro[2.4]hept-7-yl)carbamic acid benzylester (1.16 g, 16%) as an off white solid

Step 6:

To a stirred solution ofN-(trans-4-oxo-6-phenyl-5-aza-spiro[2.4]hept-7-yl)carbamic acid benzylester (3.2 g, 9.52 mmol) in MeOH (300 ml) was added 10% Pd/C (1.7 g, 50%moist) and the reaction mixture was stirred at ambient temperature undera hydrogen atmosphere using a balloon. After completion of the reaction(monitored by TLC, mobile phase 10% MeOH/DCM, R_(f) 0.2) the reactionmixture was filtered through a celite bed, which was then washed withMeOH (50 ml×2). The filtrate was concentrated under reduced pressure.The resulting residue was triturated with diethyl ether (5 ml) to affordcrude trans-7-amino-6-phenyl-5-azaspiro[2.4]heptan-4-one (1.6 g), whichwas used without further purification in the next step.

Step 7:

To a stirred suspension oftrans-7-amino-6-phenyl-5-azaspiro[2.4]heptan-4-one (1.1 g, 5.44 mmol) inDCM (25 ml) was added TEA (1.3 ml, 1.7 eq.) followed by the addition ofcyclopropanecarbonyl chloride (0.65 ml, 1.3 eq.) at 0° C. The resultingreaction mixture was then stirred for 1 h at the same temperature. Aftercompletion of the reaction (monitored by TLC, mobile phase 5% MeOH/DCM)the reaction mixture was concentrated and diluted with water. Theresulting mixture was stirred for 30 min at ambient temperature, causingprecipitation of a white solid. The solid was filtered off and waswashed with diethyl ether (10 ml×2) and was dried to afford crudeN-(trans-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)cyclopropanecarboxamide(1.2 g). The reaction was conducted in parallel in two batches. Theobtained solid from both batches batches were mixed together and werepurified by reverse phase prep HPLC to afford intermediate A5 (436.9 mg,13%) as an off white solid.

Synthesis of benzyl(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (intermediateA6)

Step 1:

To a stirred solution of acetophenone (5 g, 41.614 mmol, 1.0 eq) in EtOH(50 mL) and Hydroxylamine hydrochloride (8.68 g, 124.844 mmol, 3.0 eq),sodium acetate (17.07 g, 208.07 mmol, 5 eq) was added and the mixturewas heated to reflux for 12 h. After completion (monitored by TLC) thereaction mixture was evaporated to remove EtOH and diluted with EtOAc(2×300 mL) and water (300 mL). The extracted organic layer was washedwith brine (300 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to get crude product. The crude product was purified bycolumn chromatography (230-400 mesh silica gel, TLC system: EtOAc/hexane(2:8); R_(f)=0.3) to give (E)-1-phenylethan-1-one oxime (4.73 g, 84%).

Step 2:

To a stirred solution of (E)-1-phenylethan-1-one oxime (5 g, 36.993mmol, 1 eq) in DCM (50 mL), TEA (5.7 mL, 40.692 mmol, 1.2 eq) followedby chlorodiphenylphosphane (7.3 mL, 40.692 mmol, 1.1 eq) was added at−40° C. The reaction mixture was then stirred at RT for 16 h. Aftercompletion of reaction (monitored by TLC, 50% EtOAc in hexane,R_(f)=0.3), reaction mixture was quenched with ice and extracted withEtOAc. The organic layer was washed with water (200 mL), brine (200 mL),dried over Na₂SO₄, filtered and evaporated under reduced pressure to getthe crude product which was purified by column chromatography using230-400 silica gel and 30 to 50% EtOAc in hexane to afford(E)-P,P-diphenyl-N-(1-phenylethylidene)phosphinic amide (10.1 g, 86%) asbrown gum.

Step 3:

To a stirred solution of(E)-P,P-diphenyl-N-(1-phenylethylidene)phosphinic amide (5 g, 15.657mmol, 1 eq) in THF (75 mL), 1,4-diethyl (2E)-but-2-enedioate (6.75 g,39.143 mmol, 2.5 eq), Cu(OAc) (285 mg, 1.5657 mmol, 0.1 eq), PPh₃ (410mg, 1.5657 mmol, 0.1 eq) were added at RT and the mixture was stirred atRT for 20 min. Then pinacolborane (5.62 g, 43.839 mmol, 2.8 eq) wasadded at RT and the reaction mixture was stirred at RT for 48 h. Aftercompletion of reaction (monitored by TLC, 50% EtOAc in hexane,R_(f)=0.4), reaction mixture was diluted with EtOAc, washed with water(100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated to getthe crude product which was purified by column chromatography using230-400 silica gel and 20-40% EtOAc in hexane to afford pure desiredethyl1-(diphenylphosphoryl)-2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate(4 g, 57%).

Step 4:

To a solution of ethyl1-(diphenylphosphoryl)-2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate(5 g, 11.174 mmol, 1 eq) in EtOH (50 mL), concentrated HCl (6 ml) wasadded at RT. The mixture was stirred at 90° C. for 16 h. Aftercompletion of reaction (monitored by TLC, 50% EtOAc in Hexane,R_(f)=0.6), reaction mixture was evaporated under reduced pressure,neutralized with saturated sodium bicarbonate solution, extracted withEtOAc, dried over Na₂SO₄ and concentrated to afford ethyl2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (1.1 g, 40%) as offwhite solid.

Step 5:

To a solution of ethyl 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate(4 g, 16.1753 mmol, 1 eq) in THF:H₂O (3:1) (80 mL), LiOH.H₂O (1.36 g,32.351 mmol, 2 eq) was added at RT. The reaction mixture was stirred atRT for 16 h. After completion of reaction (monitored by TLC, 5% MeOH inDCM, R_(f)=0.1), organic solvent was evaporated under reduced pressure,dissolved in water and washed with ether and acidified with HCl. A solidprecipitate was formed, filtered, washed with water and hexane, driedover rotary evaporator to afford2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (3 g, 85%) as whitesolid.

Step 6:

To a stirred solution of 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylicacid (3 g, 13.684 mmol, 1.0 eq) in toluene (60 mL) was added TEA (2 mL,14.368 mmol, 1.05 eq) and DPPA (4.5 g, 16.4203 mmol, 1.2 eq) and thereaction mixture was stirred at 90° C. for 30 min. Then benzyl alcohol(2.8 g, 27.3672 mmol, 2.0 eq) was added to the reaction mixture and themixture was heated to reflux for 16 h. After completion (monitored byTLC, TLC system 5% MeOH in DCM, R_(f)-0.3), reaction mixture wasconcentrated under reduced pressure and diluted with EtOAc (100 mL),washed with water (2×100 mL), dried over anh. Na₂SO₄ and concentratedunder reduced pressure to get the crude product which was purified bycolumn chromatography (230-400 mesh silica gel; 0-3% MeOH in DCM) toafford benzyl (trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate(1.8 g, 41%).

Synthesis of(4S,5R)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin-2-one(intermediate A7-ent1) and(4R,5S)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin-2-one(intermediate A7-ent 2)

Step 1:

To a stirred solution of benzyl(trans-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (2.0 g, 5.91mmol) in 1,4-dioxane (100 mL) in a sealed tube was added1-(4-Fluoro-phenyl)-5-iodo-1H-indazole (2.4 g, 7.10 mmol) followed bypotassium phosphate (2.51 g, 11.83 mmol) and the mixture was degassedusing argon for 30 minutes. Then, trans-N,N′-dimethylcyclohexane-1,2-diamine (0.4 ml, 2.37 mmol) and copper(I)iodide (225 mg,1.18 mmol) were added and the mixture was heated to 100-110° C. for 16h. After completion of the reaction (monitored by LCMS, 5% MeOH in DCM),the reaction mixture was filtered through a celite bed and the celitebed was washed with 1,4-dioxane (100 mL), the filtrate was thenconcentrated under reduced pressure. The reaction was carried out in 10batches in parallel (2 g each). The combined crude material was purifiedby column chromatography (silica gel, 100-200 mesh, 2-2.5% MeOH/DCM) toafford benzyl(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate(14.5 g, 45%) as a pale yellow solid.

Step 2:

To a stirred solution of benzyl(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate(4.0 g, 7.68 mmol) in THF/MeOH (500 mL, 1:1) was added 10% Pd/C (50%moist, 2.0 g) and the resulting mixture was stirred at ambienttemperature under H₂ balloon pressure until completion of the reaction(monitored by TLC, 5% MeOH in DCM). The reaction mixture was thenfiltered through celite and the celite bed was washed with THF. Thefiltrate was then concentrated under reduced pressure. The reaction wascarried out in four batches in parallel (4 g each) and the combinedcrude material was purified by column chromatography (silica gel,100-200 mesh, 1.5-2.% MeOH/DCM as eluent) to affordtrans-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin-2-one(7.1 g, 56%) as an off-white solid.

Chiral separation (Chiralpak IC (21.0×250 mm), 5 μm, mobile phasen-hexane/EtOAc/EtOH/isopropylamine 70/15/15/0.1, flow rate 21.0 mL/min)of the racemic compound (7.1 g) in normal phase afforded (intermediateA7-ent1, retention time 6.10 minutes) and (intermediate A7-ent2,retention time 7.30 minutes).

Synthesis of methyl 2-methyl-3-nitropropanoate

Step 1: Preparation of 3-Nitro-propionic acid methyl ester: To a stirredsolution of 3-Bromo-propionic acid methyl ester (200 g, 1.19 mol) inDMSO (3 l) was added NaNO₂ (120.6 g, 1.74 mol) portion wise at 0° C. Theresulting solution was stirred at room temperature for 24 h. After thereaction was judged to be complete, the mixture was was diluted withcold brine (1.5 L) and extracted with MTBE (3×1500 ml). The combinedorganics were washed with cold water (500 ml×2), followed by brine (500ml), dried over Na₂SO₄ and concentrated under reduced pressure (bathtemp at 30 C) to afford crude 3-Nitro-propionic acid methyl ester. Thecrude material was purified by column chromatography (using silica gel100-200 mesh, 10% EA-Hexane as eluent). An oil was obtained, which wasfurther distilled under reduced pressure (120° C., 0.1-0.5 mm Hg) toafford 3-Nitro-propionic acid methyl ester (45 g, 28%) as light yellowoil.

Step 2:

methyl 2-methyl-3-nitropropanoate: To a stirred solution of3-nitro-propionic acid methyl ester (25 g, 187.97 mmol) in THF (400 ml)was added LDA (2M in THF, 188 ml, 376 mmol 2.0 eq) at −78° C. andstirred for 30 min at the same temperature. Mel (23.4 ml, 375.93 mmol,2.0 eq.) was added at −78° C. The reaction mixture was gradually warmedup to 25° C. and stirring was continued for 16 h. The reaction mixturewas quenched with aqueous NH₄Cl at 0° C. The layers were separated andthe aqueous part was extracted with ethyl acetate (600 ml×3). Thecombined organic layers were washed with brine (300 ml), dried overNa₂SO₄ and concentrated. Crude was purified by column chromatography(using 100-200 silica gel, 5-10% Ethyl acetate-Hexane as eluent) toafford methyl 2-methyl-3-nitropropanoate (10 g, 36%).

Synthesis of intermediate A8(benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate)

Step 1:

Synthesis ofrac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one:To a stirred solution of benzaldehyde (10.82 g, 102.04 mmol) in toluene(100 ml) was added 4-methoxy benzylamine (13.99 g, 102.04 mmol) at rtand stirred for 2 h at rt. To this reaction mixture was added methyl2-methyl-3-nitropropanoate (10 g, 68.03 mmol) followed by benzoic acid(12.46 g, 102.04 mmol) and stirring was continued for 16 h at 70° C.After completion of reaction (monitored by LCMS), the reaction mixturewas diluted with ethyl acetate (400 ml) and washed with water (100ml×2), followed by sat.NaHCO₃ (100 ml×2). The organic layer was driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedthrough column chromatography (using silica gel 100-200 mesh; 25-30%ethyl acetate in hexane as eluent) to affordrac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one(10 g, 43%) as brownish solid.

Step 2:

Synthesis of rac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one.To a stirred solution ofrac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one(10 g, 29.41 mmol) in acetonitrile (100 ml) was added a solution of CAN(48.37 g, 88.24 mmol) in water (100 ml) dropwise at 0° C. The reactionmixture was slowly warmed to 15° C. and stirring was continued for 3-4h. After completion (monitored by TLC, 50% ethyl acetate/hexane,R_(f)0.2), the reaction mixture was diluted with ethyl acetate (500 ml)and washed with water (100 ml×2) followed by brine (250 ml). The organiclayer was dried over Na₂SO₄ and concentrated. The crude material waspurified by column chromatography (using silica gel 100-200 mesh; 40-50%ethyl acetate in hexane as eluent) to afford ofrac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one (4.00 g, 62%)as light yellow solid.

Step 3:

Synthesis of rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one:To a stirred solution of ofrac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one (4.5 g, 20.45mmol) in EtOAc-MeOH (2:1, 450 ml) was added 6 M aq. HC (102.2 ml) at 0°C. To this reaction mixture was added Zn dust (80.25 g, 1.227 mol)portionwise at the same temperature. The resulting suspension wasstirred at room temperature for 16 h. After completion of reaction(monitorrd by LCMS), the reaction mixture was quenched with saturatedNaHCO₃ solution at 0° C., stirred for 1 h, filtered over celite andwashed with EtOAc-MeOH (500 ml, 2:1). The filtrate was concentrated toafford rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 gcrude, considered as 100% yield) which was used without furtherpurification.

Step 4:

To a stirred suspension ofrac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 g crude,20.45 mmol) in THF:Water (1:1, 225 ml) was added sodium bicarbonate(9.95 g, 118.42 mmol) at 0° C. and stirred for 30 minutes. Benzylchloroformate (11.8 ml, 35.53 mmol, 50% in toluene) was added to thereaction mixture at 0° C. and stirring was continued for 16 h at rt.After completion (monitored by LCMS), the reaction mixture was dilutedwith water (300 ml) and extracted with ethyl acetate (3×500 ml). Thecombined organics were washed with water (200 ml×2) followed by brine(200 ml) and dried over Na₂SO₄. After removal of the solvent, the crudematerial was purified by column chromatography (using silica gel 100-200mesh; 2-2.5% MeOH in DCM as eluent) to afford intermediate A8 benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (3.5 g,53% in two steps).

Synthesis of intermediate A10-trans (benzyl(rac(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate) andintermediate A10-cis (benzyl(rac(2S,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate)

Step 1:

Synthesis ofrac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one:To a stirred solution of 3-methyl-benzaldehyde (11.02 g, 91.75 mmol) intoluene (90 ml) was added 4-methoxy benzylamine (12.58 g, 91.75 mmol) atrt and stirred for 2 h. To this reaction mixture was added methyl2-methyl-3-nitropropanoate (9.00 g, 61.27 mmol) followed by benzoic acid(11.2 g, 91.75 mmol) and stirred for 16 h at 70° C. After completion ofreaction (monitored by LCMS), the reaction mixture was diluted withethyl acetate (500 ml) and washed with water (200 ml×2), followed bysat.NaHCO₃ (150 ml×2). The organic layer was dried over anhydrous Na₂SO₄and concentrated to giverac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one(7.1 g, 32.7%) as brown resin.

Step 2.

Synthesis of rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one:To a stirred solution ofrac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one(4 g, 11.28 mmol) in acetonitrile (42 ml) was added a solution of CAN(18.56 g, 33.86 mmol) in water (42 ml) dropwise at 0° C. Reactionmixture was slowly warmed to 15° C. and continued stirring was continuedfor 3-4 h. After completion (monitored by LCMS), the reaction mixturewas diluted with ethyl acetate (300 ml) and washed with water (100 ml×2)followed by brine (200 ml). The organic layer was dried over Na₂SO₄ andconcentrated. The crude material was purified by column chromatography(using silica gel 100-200 mesh; 1-1.5% MeOH in DCM)) to affordrac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one (1.5 g, 56.8%)as off white solid.

Step 3.

Synthesis of rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one:To a stirred solution ofrac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one (1.5 g, 6.37mmol) in EtOAc-MeOH (2:1, 136 ml) was added 6N aq. HCl (34 ml) at 0° C.To this reaction mixture was added Zn dust (25.01 g, 382.55 mmol) insmall portions the same temperature. The resulting suspension wasstirred at room temperature for 16 h. After completion of the reaction(monitored by LCMS), the reaction mixture was quenched with saturatedNaHCO₃ solution (until basic reaction) at 0° C., stirred for 1 h,filtered over celite and washed with EtOAc:MeOH (250 ml, 2:1). Thefiltrate was concentrated to affordrac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one (1.3 g crude,considered as 100% yield).

Step 4.

Synthesis of intermediate A10-trans and A10-cis a. To a stirredsuspension of rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one(1.3 g crude, 6.37 mmol) in THF-Water (1:1, 160 ml) was added sodiumbicarbonate (2.67 g, 31.89 mmol) at 0° C. and stirred for 30 minutes. Tothis reaction mixture was added Benzyl chloroformate (50% in toluene,3.7 ml) at 0° C. and stirred at rt for 16 h. After completion (monitoredby LCMS), the reaction mixture was diluted with water (75 ml) andextracted with ethyl acetate (3×75 ml). Combined organics were washedwith water (50 ml×2) followed by brine (50 ml×2), dried over Na₂SO₄ andconcentrated. The crude material was mixed with another batch of thesame size and was purified by column chromatography (using silica gel100-200 mesh; 1-2% MeOH in DCM as eluent) to afford intermediateA10-trans (benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate,1.39 g, 20.8% in two steps) and an impure fraction contain which wasfurther purified by prep HPLC to afford intermediate A10-cis (benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate_690mg, 10.3% in two steps).

Synthesis of intermediate A12-trans benzyl(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamateand intermediate A12-cis benzyl(rac-(2S,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate

Step 1:

Synthesis ofrac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one.To a stirred solution of 2-Chloro-benzaldehyde (11.46 g, 81.56 mmol) inToluene (80 ml) was added 4-methoxy benzylamine (11.2 g, 81.56 mmol) atrt and stirred for 2 h. To this reaction mixture was added methyl2-methyl-3-nitropropanoate (8 g, 54.37 mmol) followed by benzoic acid(9.96 g, 81.56 mmol) and stirred for 16 h at 70° C. After completion ofreaction (monitored by LCMS), the reaction mixture was diluted withethyl acetate (500 ml) and washed with water (150 ml×2), followed bysat. aq. NaHCO₃ (150 ml×2). The organic layer was dried over anhydrousNa₂SO₄ and concentrated to affordrac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one(8.2 g, 40.3%) as brown solid.

Step 2.

Synthesis ofrac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one. To astirred solution ofrac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one(8 g, 21.33 mmol) in acetonitrile (80 ml) was added an aqueous solutionof CAN (35 g, 64 mmol) in water (80 ml) dropwise at 0° C. The reactionmixture was slowly warmed to 15° C. and stirring was continued for 3-4h. After completion (monitored by LCMS), the reaction mixture wasdiluted with ethyl acetate (500 ml) and washed with water (100 ml×2)followed by brine (200 ml). The organic layer was dried over Na₂SO₄ andconcentrated. The crude material was purified by column chromatography(using silica gel 100-200 mesh; 25-30% ethyl acetate in hexane eluent)to affordrac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one (2.5 g,46%) as off white solid.

Step 3:

rac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one. To astirred solution ofrac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one (2.5 g,10.684 mol) in EtOAc/MeOH (2:1, 250 ml) was added 6 N aq. HCl (53 ml) at0° C. To this reaction mixture was added Zn dust (41.92 g, 641 mmol)portionwise at the same temperature. The resulting suspension wasstirred at room temperature for 16 h. After completion of the reaction(monitored by LCMS), the mixture was quenched with saturated NaHCO₃solution (until basic reaction) at 0° C., stirred for 1 h, filtered overcelite and washed with EtOAc/MeOH (250 ml, 2:1). The filtrate wasconcentrated to affordrac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one (2.2 gcrude, considered as 100% yield). The crude product was used withoutfurther purification in the next step.

Step 4.

Synthesis of intermediate A 12-trans and intermediate A12-cis. To astirred suspension ofrac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one (1.9 gcrude, 8.48 mmol) in THF-Water (1:1, 100 ml) was added sodiumbicarbonate (3.56 g, 86.36 mmol) at OoC and the mixture was stirred for30 minutes. To this reaction mixture was added benzyl chloroformate (50%in toluene, 4.3 ml) at 0° C. and stirred at rt for 16 h. After thereaction was judged to be complete (monitored by LCMS), the reactionmixture was diluted with water (100 ml) and extracted with ethyl acetate(3×100 ml). The combined organic layers were washed with water (100ml×2) followed by brine (100 ml), dried over Na₂SO₄ and concentrated.The crude product was mixed with another 1.5 g batch and the combinedmaterial was purified by column chromatography (using silica gel 100-200mesh; 1-2% MeOH in DCM as eluent) to afford an mixture of isomers ofintermediate A12-trans and intermediate A12-cis (3.3 g). Prep HPLCpurification afforded intermediate A12-trans benzyl(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(815 mg, 14.9%, in two steps, after prep-purification) and anotherfraction (1.7 g) which was further purified further by prep HPLC toafford intermediate A12-cis benzyl(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(810 mg, 14.8%).

Synthesis of intermediate A14 benzyl(rac-(2R,3S,4S)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate

Step 1:

Synthesis ofrac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one.To a stirred solution of 4-methoxy-benzaldehyde (13.88 g, 101.95 mmol)in toluene (100 ml) was added 4-methoxybenzyl amine (13.98 g, 101.95mmol) at rt and the mixture was stirred for 2 h. To this reactionmixture was added 2-methyl-3-nitropropanoate (10.0 g, 67.96 mmol)followed by benzoic acid (12.45 g, 101.95 mmol) and stirred for 16 h at70° C. After completion of the reaction (monitored by LCMS), the mixturewas diluted with ethyl acetate (250 ml) and washed with water (100 ml),followed by sat. aq. NaHCO₃ (100 ml×2). The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The crude material was purified bycolumn chromatography (using silica gel 100-200 mesh; 20-25% ethylacetate/hexanes eluent)rac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one(11.5 g, 45.7%) as brown solid.

Step 2.

Synthesis ofrac-(3S,4S,5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one. Toa stirred solution ofrac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one(14.5 g, 39.04 mmol) in acetonitrile (150 ml) was added a solution ofCAN (64.2 g, 117.12 mmol) in water (150 ml) dropwise at 0° C. Thereaction mixture was slowly warmed up to 15° C. and stirring wascontinued for 3-4 h. After the starting material was consumed (monitoredby TLC, 50% ethyl acetate/hexane, R_(f) 0.2), the reaction mixture wasdiluted with ethyl acetate (300 ml) and washed with water (100 ml×2)followed by brine (150 ml). The organic layer was dried over Na₂SO₄ andconcentrated. The crude material was purified by column chromatography(using silica gel 100-200 mesh; 20-30% ethyl acetate/hexane eluent) toaffordrac-(3S,4S,5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one(3.82 g, 39%) as light yellow solid.

Step 3.

Synthesis ofrac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one. Toa stirred solution ofrac-(3S,4S,5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one (3.8g, 15.2 mmol) in EtOAc/MeOH (2:1, 380 ml) was added 6N aq. HCl (76 ml)at 0° C. To this reaction mixture was added Zn dust (59.64 g, 912 mmol)portionwise at the same temperature. The resulting suspension wasstirred at room temperature for 16 h. After completion of the reaction(monitored by LCMS), the reaction mixture was quenched with saturatedNaHCO₃ solution at 0° C., stirred for 1 h, filtered over celite andwashed with EtOAc/MeOH (300 ml, 2:1). The filtrate was concentrated toaffordrac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one(3.52 μg crude, considered as 100% yield). The crude product was used inthe next step without further purification.

Step 4:

To a stirred suspension ofrac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one(3.52 g crude, 15.2 mmol) in THF-Water (1:1, 200 ml) was added sodiumbicarbonate (7.25 g, 86.36 mmol) at 0° C. and stirred for 30 minutes. Tothis reaction mixture was added benzyl chloroformate (50% in toluene,8.66 ml) at 0° C. and stirring was continued at rt for 16 h. Aftercompletion (monitored by LCMS), the reaction mixture was diluted withwater (100 ml) and extracted with ethyl acetate (3×150 ml). The combinedorganics were washed with water (150 ml×2) followed by brine (200 ml),dried over Na₂SO₄ and concentrated. The crude material was purified bycolumn chromatography (using silica gel 100-200 mesh; 1-2% MeOH in DCMas eluent) to intermediate A14 as an off-white solid. (2.5 g, 39% in twosteps)

Synthesis of Intermediate A16 benzyl(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate

Step-1:

Synthesis ofrac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one.To a stirred solution of 5-chloro-thiophene-2-carbaldehyde (10 g, 0.068mol) in toluene (250 ml) was added 4-methoxy benzylamine (10.26 g,0.0748 mol) at rt and stirred for 2 h. To this reaction mixture wasadded 2-methyl-3-nitropropanoate (11 g, 0.0748 mol) followed by benzoicacid (12.46 g, 0.102 mol) and stirred at 80° C. for 16 h. Aftercompletion of the reaction (monitored by TLC, 30% EA/Hexane), thereaction mixture was diluted with ethyl acetate (200 ml) and washed withwater (500 ml), followed by sat. aq. NaHCO₃(300 ml×3). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated. The obtained crudematerial was purified through column chromatography (using silica gel100-200 mesh; 25-30% ethyl acetate/hexane eluent) to affordrac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one(8 g, 28%) as a brown resin.

Step-2:

Synthesis ofrac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one.To a stirred solution ofrac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one(5 g, 0.013 mol) in CH₃CN (50 ml) was added a solution of CAN (21.38 g,0.039 mol) in water (50 ml) dropwise at 0° C. the reaction mixture wasstirred at same temperature for 2 h. After completion (monitored by TLCin 50% EA-Hexane, R_(f) 0.3), the reaction mixture was diluted withethyl acetate and washed with water followed by brine. The organic layerwas dried over Na₂SO₄ and concentrated. The obtained crude material waspurified by column chromatography (using silica gel 100-200 mesh, 70%EA-hexane as eluent) to obtainrac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one(2.3 g, 82%) as off white solid.

Step-3:

Synthesis ofrac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one.To a stirred solution ofrac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one(1.8 g, 6.9 mmol) in EtOAc/MeOH (360 ml, 2:1) was added 6 N aq. HCl (35ml) at 0° C. To the mixturewas added Zn dust (27.07 g, 414 mmol)portionwise at the same temperature. The resulting suspension wasstirred at room temperature for 16 h. After completion (monitored byLCMS), the reaction mixture was quenched with saturated NaHCO₃ solutionat 0° C., stirred for 1 h, filtered over celite and washed withEtOAc/MeOH (500 ml, 2:1). The filtrate was concentrated to affordrac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one(1.6 g, crude) as off white solid. The crude product was used in thenext step without further purification.

Step-4:

Synthesis of intermediate A16: To a stirred suspensionrac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one(3 g, 0.013 mol) in THF/Water (60 ml, 1:1) was added sodium bicarbonate(5.46 g, 0.065 mol) at 0° C. and stirred for 30 minutes. To this wasadded benzyl chloroformate (50% solution in toluene, 6.65 g, 0.0195 mol)at the same temperature and stirring was continued at rt for 16 h. Aftercompletion (monitored by LCMS), the reaction mixture was diluted withwater (100 ml) and extracted with ethyl acetate (3×90 ml). The combinedorganics were washed with water (90 ml) followed by brine (90 ml). Theorganic layer was dried over Na₂SO₄ and concentrated. Crude material waspurified by column chromatography (using silica gel 100-200 mesh; 2-2.5%MeOH/DCM eluent) to afford intermediate A16 benzyl(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(3 g, 79% in 2 steps) as off-white solid.

Synthesis of intermediate A18 benzyl(rac-(2S,3S,4S)-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidin-3-yl)carbamate

Step-1:

Preparation ofrac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4-nitropyrrolidin-2-one.To a stirred solution of 1-methyl-1H-pyrazole-3-carbaldehyde (5 g, 45.46mmol) in Toluene (75 ml) was added 4-methoxy benzylamine (6.86 g, 50.01mmol) at rt and stirred for 2 h. To this reaction mixture was added2-methyl-3-nitropropanoate (8.68 g, 59.09 mmol) followed by benzoic acid(8.33 g, 687.18 mmol) and stirring was continued for 16 h at 70° C.After completion of the reaction (monitored by LCMS), the reactionmixture was diluted with ethyl acetate (200 ml) and washed with water(200 ml), followed by sat. aq. NaHCO₃ (75 ml×2). The organic layer wasdried over anhydrous Na₂SO⁴ and concentrated. Crude was purified bycolumn chromatography (using silica gel 100-200 mesh; 25-30% ethylacetate/hexane eluent) to affordrac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4-nitropyrrolidin-2-one(4 g, 26%) off white solid.

Step-2:

Preparation of rac-(3S,4S,5S)-3-methyl-5-(1-methyl-iH-pyrazol-3-yl)-4-nitropyrrolidin-2-one. To a stirred solution ofrac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4-nitropyrrolidin-2-one(2 g, 5.814 mmol) in CH₃CN (40 ml) was added a solution of CAN (6.37 g,11.63 mmol) in water (40 ml) dropwise at 0° C. The reaction mixture wasstirred at same temperature for 2 h. After completion (monitored by TLCin 50% EA-Hexane, R_(f) 0.3), the reaction mixture was diluted withethyl acetate and washed with water followed by brine. The organic layerwas dried over Na₂SO₄ and concentrated. Two more identical batches wereconducted using the procedure described above. The crude material of thecomposite batch was purified by column chromatography (using silica gel100-200 mesh, 70% EA-hexane as eluent) to affordrac-(3S,4S,5S)-3-methyl-5-(1-methyl-H-pyrazol-3-yl)-4-nitropyrrolidin-2-one(2.4 g, 61.4%) as off white solid.

Step-3:

Preparation ofrac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one.To a stirred solutionofrac-(3S,4S,5S)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4-nitropyrrolidin-2-one(2.5 g, 11.16 mmol) in EtOAc/MeOH (2; 1, 200 ml) was added aq. 6 N HCl(56 ml) at 0° C. To this reaction mixture was added Zn dust (43.8 g,669.64 mmol) portionwise at the same temperature. The resultingsuspension was stirred at room temperature for 16 h. After completion(monitored by TLC in 10% MeOH-DCM, R_(f) 0.4), the reaction mixture wasquenched with saturated aq. NaHCO₃ solution at 0° C. and filtered overcelite, washed with EtOAc/MeOH (500 ml, 2:1) and concentrated to affordrac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one(2.5 g, crude). The crude product was used in the next step withoutfurther purification.

Step-4:

Preparation of intermediate A18: To a stirred suspension ofrac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one(2.5 g crude, 12.87 mmol) in THF/Water (1; 1, 250 ml) was added sodiumbicarbonate (5.41 g, 64.43 mmol) at 0° C. and stirred for 30 minutes. Tothis reaction mixture was added benzyl chloroformate (6.4 ml, 19.32mmol, 50% in toluene) at 0° C. and stirred at rt for 16 h. Aftercompletion of the reaction (monitored by LCMS), the mixture was dilutedwith water (500 ml) and extracted with ethyl acetate (3×500 ml). Thecombined organic layers were washed with water (250 ml×2) followed bybrine (500 ml). Organic part was dried over Na₂SO₄ and concentrated.Crude material was purified by column chromatography (using silica gel100-200 mesh; 2-2.5% MeOH/DCM as eluent) to afford intermediate A18benzyl(rac-(2S,3S,4S)-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidin-3-yl)carbamate(1.99 g, 54.3% in two steps) as off white solid.

Synthesis of intermediate A20 benzyl(rac-(2R,3S,4S)-4-benzyl-2-ethyl-5-oxopyrrolidin-3-yl)carbamate

Step-1:

Synthesis of methyl 2-benzyl-3-nitropropanoate. To a stirred solution ofLDA (2 M in THF, 22.5 ml, 45.09 mmol) in THF (30 ml) was added asolution of methyl 3-nitropropanoate (3 g, 22.54 mmol) and DMPU (27.3ml, 222.49 mmol) in THF (20 ml) at −78° C. and stirring was continuedfor 30 minutes at the same temperature. A solution of(bromomethyl)benzene (2.69 ml, 22.54 mmol) in THF (15 ml) was added at−78° C. and stirred for 2 h at the same temperature. The mixture wasgradually allowed to reach 25° C. and stirred for 16 h. The reactionmixture was quenched with 1 N HCl (100 ml) at 0° C. and extracted withethyl acetate (100 ml×2). The combined organic layers were washed withwater (100 ml), saturated aqueous NaHCO₃ solution (100 ml) followed bybrine (100 ml), dried over Na₂SO₄ and concentrated. The crude productwas purified by column chromatography (using 100-200 silica gel, 10-12%Ethyl acetate-Hexane as eluent) to afford methyl2-benzyl-3-nitropropanoate (3.3 g, 65.65%) as light yellow oil.

Step-2:

Synthesis ofrac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-one.To a stirred solution of propionaldehyde (3.61 ml, 50.39 mmol) intoluene (75 ml) was added 4-methoxy benzylamine (6.91 g, 50.39 mmol) at25° C. and stirring was continued for 2 h. To this reaction mixture wasadded methyl 2-benzyl-3-nitropropanoate (7.5 g, 33.59 mmol) followed bybenzoic acid (6.15 g, 50.39 mmol) and stirred for 7-8 h at 70° C. Aftercompletion of the reaction (monitored by TLC, 30% EA/Hexane, R_(f)=0.4),the reaction mixture was diluted with ethyl acetate (300 ml) and washedwith water (300 ml), followed by sat. aq. NaHCO₃ (200 ml×2). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was purified bycolumn chromatography (using silica gel 100-200mesh; 25-30% ethyl acetate/hexane eluent) to affordrac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-one(3.5 g, 28.3%) as brown oil.

Step-3:

Synthesis of rac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitropyrrolidin-2-one. Toa stirred solution ofrac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-one(3.6 g, 9.77 mmol) in acetonitrile (36 ml) was added a solution of CAN(16.1 g, 29.31 mmol) in water (36 ml) dropwise at 0° C. The reactionmixture was slowly warmed up to 10-15° C. and stirring was continued for3-4 h. After completion of the reaction (monitored by TLC, 40% acetonein hexanes, R_(f) 0.3), the mixture was diluted with ethyl acetate (200ml) and washed with water (200 ml) followed by brine (200 ml). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude materialwas purified by column chromatography (using silica gel 100-200 mesh;35-40% ethyl acetate/hexanes as eluent) to affordrac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitropyrrolidin-2-one (1.53 g, 63%) aslight yellow solid.

Step-4:

Synthesis of rac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one. Toa stirred solution ofrac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitropyrrolidin-2-one (2.8 g, 11.27mmol) in EtOAc/MeOH (252 ml, 2:1) was added 6M aq. HCl solution (80 ml)at 0° C. To this was added Zn dust (44.24 g, 676.68 mmol) portionwise atthe same temperature. The resulting suspension was stirred at roomtemperature for 16 h. After completion of the reaction (monitored byLCMS), the reaction mixture was quenched with saturated NaHCO₃ solutionat 0° C., stirred for 1 h, filtered over celite and washed withEtOAc/MeOH (300 ml, 2:1). Filtrate was concentrated to affordrac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one (2.43 g crude,considered as 100% yield) as off white solid which was used in next stepas such.

Step-5:

Synthesis of intermediate A20: To a stirred suspension ofrac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one (2.43 g crude11.18 mmol) in THF/Water (300 ml, 1:1) was added sodium bicarbonate(4.69 g, 55.91 mmol) at 0° C. and stirred for 30 minutes. To this wasadded benzyl chloroformate (5.58 ml, 16.77 mmol, 50% in toluene) at 0°C. and stirred at rt for 16 h. After completion of the reaction(monitored by LCMS), the reaction mixture was diluted with water (300ml) and extracted with ethyl acetate (3×300 ml). The combined organiclayers were washed with water (300 ml) followed by brine (300 ml), driedover Na₂SO₄ and concentrated. The crude product was purified by columnchromatography (using silica gel 100-200 mesh; 1.5-2% MeOH/DCM eluent)to afford intermediate A20 benzyl(rac-(2R,3S,4S)-4-benzyl-2-ethyl-5-oxopyrrolidin-3-yl)carbamate (2.95 g,74.9%) as off white solid.

Synthesis of intermediate A9rac-(3S,4S,5R)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methyl-5-phenylpyrrolidin-2-one

Step 1:

Synthesis of benzylN-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]carbamate.In a microwave vial, benzylN-[rac(2R,3S,4S)-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]carbamate (500mg, 1.54 mmol) was added to 1-(4-fluorophenyl)-5-iodo-indazole (537 mg,1.70 mmol), K₃PO₄ (654 mg, 3.08 mmol) and CuI (58.7 mg, 0.308 mmol). Thevial was sealed and purged with nitrogen. To the mixture, 1,4-dioxane(15.4 mL), followed by (1R,2R)—N,N′-Dimethyl-1,2-cyclohexandiamine (87.7mg, 0.617 mmol) were added subsequently. The mixture was heated to 100°C. overnight and to 110° C. for 5 h afterwards. After reaction control(UPLC) showed full conversion of the starting material, the slurry wasallowed to cool down to room temperature and ethyl acetate followed bysat. NaHCO₃-solution were added. The mixture was stirred for 5 minutes,the layers were separated and the aqueous layer was extracted with ethylacetate once. The combined organic layers were washed with brine anddried over MgSO₄. Flash chromatography (40 g silica-cartridge,cyclohexane/ethyl acetate gradient as eluent) of the crude material gaveN-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]carbamate(465 mg, 0.870 mmol, 56%) as a white solid.

Step 2.

A solution ofN-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]carbamate(465 mg, 0.870 mmol) in acetonitrile (23 ml) was added to NaI (783 mg,5.22 mmol) in a sealed tube. To this mixture, trimethylsilyl chloride(0.442 mL, 3.48 mmol) was added dropwise. The reaction mixture wasstirred at room temperature overnight and was slowly added to ethanol(28 ml) after reaction control showed completion (UPLC). The resultingsolution was charged on a 5 g SCX cartridge, washed two times withethanol (15 ml each) and eluated with 2M ammonia in methanol. Themethanolic fractions were combined. Evaporation of the solvent gave(rac-3S,4S,5R)-4-amino-1-[1-(4-fluorophenyl)indazol-5-yl]-3-methyl-5-phenyl-pyrrolidin-2-oneintermediate A9 (316 mg, 0.789 mmol, 91%) as a white solid.

The intermediates in the following table were synthesized in analogy tointermediate 9 described above, using different building blocks

Intermedi- ate # Structure Made of A11-trans

Intermediate A-10-trans A11-cis

Intermediate A-10-cis A13-trans

Intermediate A12-trans A13-cis

Intermediate A12-cis A19

Intermediate A18 A21

Intermediate A20

Synthesis of intermediates A15-cis benzyl(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamateand intermediate A15-trans benzyl(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate

Step 1:

Synthesis of benzyl(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamateand benzyl(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.In a microwave vial, intermediate A14 (500 mg, 1.54 mmol) was added to1-(4-fluorophenyl)-5-iodo-indazole (524 mg, 1.55 mmol, 1.1 eq.), K₃PO₄(599 mg, 2.82 mmol, 2.0 eq.) and CuI (53.7 mg, 0.282 mmol, 0.2 eq.). Thevial was sealed and purged with nitrogen. To the mixture 1,4-dioxane(14.1 mL), followed by (1R,2R)—N,N′-Dimethyl-1,2-cyclohexandiamine (80.3mg, 0.564 mmol, 0.4 eq.) were added subsequently. The mixture was heatedto 100° C. overnight and to 110° C. for 5 h. After reaction control(UPLC) showed full conversion of the starting material, the slurry wasallowed to cool down to room temperature and ethyl acetate followed bysat. NaHCO₃-solution were added. The mixture was stirred for 5 minutes,the layers were separated and the aqueous layer was extracted with ethylacetate once. The combined organic layers were washed with brine anddried over MgSO₄. Flash chromatography (40 g silica-cartridge,cyclohexane/ethyl acetate gradient as eluent) of the crude material gavebenzyl(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(545 mg, 0.965 mmol, 68%) and the epimer benzyl(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(116 mg, 0.206 mmol, 15%).

Step 2:

According to the procedure described for intermediate A9, step 2,(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamatewas used to obtain intermediate A15-trans benzyl(rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.

Step 3:

According to the procedure described for intermediate A9, step 2,(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamatewas used to obtain intermediate A15-cis benzyl((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.

Synthesis of intermediate A17-cis(3R,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-oneand intermediate A17-trans(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-one

Step 1:

Synthesis of benzyl(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamateand benzyl(rac-(2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate:In analogy to the procedure described for intermediates A15-trans andA15-cis step 1, intermediate A16 (500 mg, 1.37 mmol) was coupled with1-(4-fluorophenyl)-5-iodo-indazole (510 mg, 1.51 mmol, 1.1 eq) to obtainbenzyl(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(644 mg, 1.12 mmol, 82%) and the epimer benzyl(rac-(2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate(118 mg, 0.205 mmol, 15%).

Step 2:

According to the procedure described for intermediate A9, step 2,((2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamatewas deprotected to obtain intermediate A17-trans(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-one.

Step 3:

According to the procedure described for intermediate A9, step 2,((2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamatewas deprotected to obtain intermediate A17-cis(3R,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-one.

Synthesis of 1-(4-fluorophenyl)-5-iodo-1H-indole (intermediate B1)

Step 1:

5-Bromo-1H-indole (750.0 mg, 3.826 mmol, 1.0 eq.),1-fluoro-4-iodo-benzene (891.7 mg, 4.017 mmol, 1.05 eq.), K₃PO₄ (1624.1mg, 6.513 mmol, 2.0 eq.) and copper iodide (582.9 mg, 3.061 mmol, 0.8eq.) were weighed out into a vial, a stir bar was added, the vial wassealed and was purged with nitrogen. Then, 1,4-dioxane (19.1 mL) andtrans-N,N-dimethyl cyclohexane-1,2-diamine (54.4 mg, 0.3826 mmol, 0.1eq.) were added, and the reaction mixture was heated to 100° C. for 16h. The reaction mixture was then cooled to ambient temperature, wasdiluted with DCM and sat. NaHCO₃ solution and was filtered through ahydrophobic frit. The organic solvent was removed, and the remains werepurified via silica gel chromatography to yield5-bromo-1-(4-fluorophenyl)-1H-indole in 35% yield.

Step 2:

5-Bromo-1-(4-fluorophenyl)indole (2300 mg, 7.927 mmol, 1.0 eq.), NaI(5941 mg, 39.6 mmol, 5.0 eq.) K₃PO₄ (3365 mg, 15.8 mmol, 2.0 eq.) andcopper iodide (1207 mg, 6.3419 mmol, 0.8 eq.) were weighed out into aflask, a stir bar was added, the vial was sealed and was purged withnitrogen. Then, 1,4-dioxane (58.4 mL) and trans-N,N-dimethylcyclohexane-1,2-diamine (112.8 mg, 0.793 mmol, 0.1 eq.) were added, andthe reaction mixture was heated to 100° C. for one week. The reactionmixture was then cooled to ambient temperature, was diluted with DCM andsat. NaHCO₃ solution and was filtered through a hydrophobic frit. Theorganic solvent was removed, and the remains were purified via silicagel chromatography to yield 1580 mg of intermediate B1 (53%).

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine(intermediate B2)

Step 1:

Intermediate B2 was prepared in analogy to the synthesis of intermediateB4, using 5-bromo-2-fluoro-pyridine-3-carbaldehyde instead of6-bromo-3-fluoro-pyridine-2-carbaldehyde. Yield: 66%

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine(intermediate B3)

Step 1:

Intermediate B3 was prepared in analogy to the synthesis of intermediateB4, using 2-bromo-5-fluoro-pyridine-4-carbaldehyde instead of6-bromo-3-fluoro-pyridine-2-carbaldehyde. Yield: 79%

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(intermediate B4)

Step 1:

6-Bromo-3-fluoro-pyridine-2-carbaldehyde (300.0 mg, 1.471 mmol, 1.0 eq.)and (4-fluorophenyl)hydrazine hydrochloride (239.1 mg, 1.471 mmol, 1.0eq.) were dissolved in NMP (3.0 mL) and the resaction mixture wasstirred for 90 minutes. Then, Cs₂CO₃ (1437.8 mg, 4.412 mmol, 3.0 eq.)was added and the reaction mixture was heated to 115° C. for 90 minutes.The reaction mixture was then allowed to warm to ambient temperature,and was diluted with EtOAc and water. The layers were separated, and theaqueous phase was extracted two time with EtOAc. The combined organiclayers were washed with water and brine, dried over MgSO₄ and thesolvent was removed under reduced pressure. The obtained residue wasthen purified by LC to yield 297.0 mg (69%) of5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine.

Synthesis of intermediate C1N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

Step 1:

Maleic anhydride (9.8 g, 100 mmol, 1.0 eq), p-thiocresol (12.4 g, 100mmol, 1.0 eq), ammonium acetate (7.8 g, 100 mmol, 1.0 eq) andbenzaldehyde (10 mL, 100 mmol, 1.0 eq) were put in a sealed tube and 100ml toluene was added. The reaction mixture was stirred at RT for 1 h andthen stirred at 150° C. for 16 h. After cooling to RT, the solvent wasevaporated under reduced pressure, and the residue was basified withsat.NaHCO₃ solution and was extracted with DCM. The aqueous layer wasacidified with 2N HCl under ice cooling and the crude product wasextracted twice with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to get the crude5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylic acid (10.0 g,crude).

Step 2:

To a stirred solution of crude5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylic acid (10.0 g,30.58 mmol, 1.0 eq) in acetone (100 mL), potassium carbonate (16.8 g,122.32 mmol, 4.0 eq) and methyl iodide (7.6 ml, 122.32 mmol, 4.0 eq)were added at 0° C., and the reaction was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, and the residue waspartitioned between DCM and water. The aqueous layer was extracted twicewith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude product was purified bycolumn chromatography (100-200 silica gel, 50% EtOAc:hexanes) to givemethyl 5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate (4.0 g,38%) as an off-white solid.

Step 3:

To a stirred solution of methyl5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate (4.0 g, 11.73mmol, 1.0 eq) in EtOH:THF (100 mL, 2:1), Raney Nickel (1 g) was addedand the reaction mixture was stirred for 2 h at RT After completion, thereaction mixture was filtered through a celite bed and the celite bedwas washed 2-3 times with EtOAc. The combined organic layers wereconcentrated and the crude was purified by column chromatography(100-200 silica gel, 50% EtOAc:hexanes) to afford methyl5-oxo-2-phenylpyrrolidine-3-carboxylate (2.2 g, 88%, syn: anti, 1:1mixture) as an off-white solid.

Step 4:

To a stirred solution of methyl 5-oxo-2-phenylpyrrolidine-3-carboxylate(1.0 g, 4.56 mmol, 1.0 eq) in MeOH (25 mL) was added 2 NNaOH solution (5mL) and the reaction mixture was stirred at 80° C. for 2 h. Aftercompletion of the reaction (monitored by LCMS), the reaction mixture wasconcentrated and acidified with 2N HCl solution and was extracted with30% isopropanol-DCM. The combined organic layers were dried over Na₂SO₄and were concentrated under reduced pressure to get the desiredtrans-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (0.8 g, 85%).

Step 5:

To a stirred solution of trans-5-oxo-2-phenylpyrrolidine-3-carboxylicacid (0.5 g, 2.43 mmol, 1.0 eq) in benzene:THF (25 mL, 4:1) was addedTEA (0.68 ml, 4.87 mmol, 2.0 eq) and DPPA (0.68 ml, 3.17 mmol, 1.3 eq)and the reaction mixture was stirred at RT for 2 h. Then benzyl alcohol(0.33 mL, 3.17 mmol, 1.3 eq) was added and the reaction mixture washeated to reflux for 16 h. After completion, the reaction mixture wasconcentrated under reduced pressure to get the crude compound which wasextracted with water and EtOAc. The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to get the crudeproduct which was purified by column chromatography (100-200 mesh silicagel; 2% MeOH-DCM; R_(f)-value-0.5) to afford trans-benzyl(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (0.38 g, 50%).

Step 6:

To a stirred solution of trans-benzyl(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (1.7 g, 5.48 mmol, 1.0 eq) inMeOH (20 mL, 2:1), Pd/C (0.058 g, 0.548 mmol, 0.1 eq) was added, and thereaction was stirred with a hydrogen balloon for 2 h at RT. Aftercompletion, the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with EtOAc. The combined organiclayers were concentrated to get the desiredtrans-4-amino-5-phenylpyrrolidin-2-one as brown gum (0.9 g, 93%).

Step 7:

To a stirred solution of cyclopropanecarboxylic acid (0.59 g, 6.818mmol, 1.2 eq) in DMF (15 mL) was added HATU (4.32 g, 11.363 mmol, 2.0eq), DIPEA (5.0 mL, 28.409 mmol, 5.0 eq) and intermediate A2 (1.00 g,5.681 mmol, 1.0 eq) at 0° C. and the reaction mixture was then stirredat ambient temperature for 16 h. After completion of the reaction(monitored by TLC, TLC system 5% MeOH in DCM, R_(f)-0.3), the reactionmixture was diluted with EtOAc (35 mL) and was washed with ice coldwater (3×25 mL), dried over Na₂SO₄ and concentrated under reducedpressure to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0 to 4% MeOH-DCM) to affordN-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.45 g,32%).

Step 8:

A stirred solution ofN-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.450 g,1.844 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.748 g,2.213 mmol, 1.2 eq) and K₃PO₄ (0.781 g, 3.688 mmol, 2.0 eq) in1,4-dioxane (30 mL) was degassed with argon for 30 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.104 g, 0.737 mmol, 0.4 eq)and CuI (0.070 g, 0.368 mmol, 0.2 eq) were added and the reactionmixture was stirred for 16 h at 90° C. in a sealed tube. Aftercompletion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM,R_(f)-0.4), the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with 1,4-dioxane. The combinedorganic layers were concentrated to get the crude product which waspurified by column chromatography (230-400 mesh silica gel; 0 to 2% MeOHin DCM) to afford the racemic product. Further enantiomer separation wasdone by preparative chiral HPLC to afford pureN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(0.267 g, 32%; RT=5.56 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/Isopropanol/DCM/DEA: 70/15/15/0.1, Flow Rate: 1.0ml/min) and intermediate C₁—ent1N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(0.254 g, 30%; RT=7.13 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/Isopropanol/DCM/DEA: 70/15/15/0.1, Flow Rate: 1.0ml/min).

EXAMPLES 1 AND 2N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(example 1) andN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(example

Step 1:

A stirred solution of intermediate A2 (0.35 g, 1.286 mmol, 1.0 eq),1-(4-fluorophenyl)-5-iodo-1H-indazole (0.520 g, 1.54 mmol, 1.2 eq),K₃PO₄ (0.545 g, 2.572 mmol, 2.0 eq) in 1,4 dioxane (20 mL) was degassedwith argon for 30 min. Then, trans-N,N′-dimethyl cyclohexane-1,2-diamine(0.073 g, 0.514 mmol, 0.4 eq) and CuI (0.049 g, 0.257 mmol, 0.2 eq) wereadded and the reaction was stirred for 16 h at 90° C. in a sealed tube.After completion of the reaction (monitored by TLC, TLC system 5% MeOHin DCM, Rf-0.4) the reaction mixture was filtered through a celite pad,which was then washed 2-3 times with 1,4-dioxane. The combined organiclayers were concentrated to obtain the crude product which was purifiedby column chromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM)to afford the racemic compound and further enantiomer separation wascarried out via prep. chiral HPLC (column: Chiralpak IC (4.6×250 mm), 5μm, mobile phase: hexane:ethyl acetate:EtOH:isopropylamine 70:15:15:0.1,flow rate: 1.0 mL/min) to afford example 1 (0.055 g, 9%, retention time:4.62 minutes) and example 2 (0.057 g, 9%, retention time 6.48 minutes).

¹H NMR (400 MHz, DMSO-d₆): δ=8.46 (d, 1H), 8.29 (s, 1H), 7.74-7.71 (m,3H), 7.67 (d, 1H), 7.46 (m, 1H), 7.39 (d, 2H), 7.34-7.32 (m, 2H), 7.22(t, 2H), 7.14 (t, 2H), 5.11 (d, 1H), 4.29 (t, 1H), 1.69-1.63 (m, 1H),1.21 (s, 3H), 1.12 (s, 3H), 0.7-0.52 (m, 4H).

EXAMPLE 5N-trans-(5-(1-(4-fluorophenyl)-1H-indol-5-yl)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)cyclopropanecarboxamide

Step 1:

Intermediate A5 (50.0 mg, 0.185 mmol, 1.0 eq.), intermediate B1 (65.5mg, 0.194 mmol, 1.05 eq.), K₃PO₄ (78.5 mg, 0.370 mmol, 2.0 eq.) andcopper iodide (28.2 mg, 0.148 mmol, 0.8 eq.) were weighed out into avial, a stir bar was added, the vial was sealed and was purged withnitrogen. Then, 1,4-dioxane (0.9 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (2.5 mg, 0.019 mmol, 0.1 eq.) were added, andthe reaction mixture was heated to 100° C. for six days. The reactionmixture was then cooled to ambient temperature, was diluted with DCM andsat. NaHCO₃ solution and was filtered through a hydrophobic frit. Theorganic solvent was removed, and the remains were purified via silicagel chromatography to yield 4.0 mg (4%) of example 5.

¹H NMR (DMSO-d₆) δ: 8.88 (d, 1H), 7.74-7.70 (m, 1H), 7.62-7.54 (m, 3H),7.45-7.35 (m, 6H), 7.33 (dd, 2H), 7.27-7.19 (m, 1H), 6.63 (d, 1H), 5.22(d, 1H), 4.01 (dd, 1H), 1.72-1.64 (m, 1H), 1.28-1.05 (m, 2H), 0.97-0.89(m, 2H), 0.79-0.73 (m, 1H), 0.73-0.68 (m, 3H).

EXAMPLE 7N-((2R,3S)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-5-methylisoxazole-3-carboxamide

Step 1:

5-Methylisoxazole-3-carboxylic acid (22.3 mg, 0.175 mmol, 1.5 eq.) wasdissolved in DCM (1.2 mL), followed by the addition of triethylamine(0.05 mL, 0.351 mmol, 3.0 eq.). Then propylphosphonic anhydride solution(>50 wt. % in ethyl acetate, 0.14 mL, 2.0 eq.) was added, and themixture was stirred at ambient temperature for 20 minutes. Then,intermediate A4 ent1 (50.0 mg, 0.117 mmol, 1.0 eq.), was added, and themixture was stirred for 48 hours at ambient temperature. Then, saturatedNaHCO₃ solution and more DCM were added, and the mixture was stirred for10 minutes. The mixture was then filtered through a hydrophobic frit,and the organic solvent was then removed. The crude remains werepurified via silica gel chromatography to yield 36.0 mg (57%) of example7.

¹H NMR (DMSO-d₆) δ: 9.09 (d, 1H), 8.26 (d, 1H), 8.17 (d, 1H), 7.72-7.67(m, 2H), 7.59 (d, 1H), 7.39 (dd, 1H), 7.38-7.36 (m, 2H), 7.26-7.20 (m,2H), 7.18-7.12 (m, 1H), 6.54 (d, 1H), 6.51 (d, 1H), 5.50 (d, 1H), 4.47(t, 1H), 3.50 (s, 3H), 2.47 (d, 3H), 1.32 (s, 3H), 1.17 (s, 3H).

EXAMPLE 31N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide

Step 1:

5-Bromo-1-(4-fluorophenyl)pyrazolo[3,4-b]pyridine (64.8 mg, 0.222 mmol,1.2 eq.), intermediate A5 (50.0 mg, 0.185 mmol, 1.0 eq.), K₃PO₄ (78.5mg, 0.370 mmol, 2.0 eq.), CuI (7.0 mg, 0.037 mmol, 0.2 eq.) and NaI(55.4 mg, 0.370 mmol, 2.0 eq.) were weighed out into a microwave vial. Astir bar was added, the vial was sealed and purged with nitrogen. Then,1,4-dioxane (1.0 mL) and trans-N,N′-dimethyl cyclohexane-1,2-diamine(0.012 mL, 0.074 mmol, 0.4 eq.) were added and the mixture was stirredat 110° C. for 16 hours. The mixture was then allowed to cool to ambienttemperature and was diluted with sat. NaHCO₃ solution and DCM. Themixture was then filtered through a hydrophobic frit. The organic layerwas evaporated under reduced pressure and the residue was purified viaLC to yield 42.0 mg (47%) ofN-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide

¹H NMR (DMSO-d₆): δ=8.92-8.86 (m, 2H), 8.44 (d, 1H), 8.40 (s, 1H),8.25-8.16 (m, 2H), 7.44-7.37 (m, 4H), 7.35 (t, 2H), 7.29-7.23 (m, 1H),5.37 (d, 1H), 4.13 (dd, 1H), 1.71-1.63 (m, 1H), 1.25 (dd, 1H), 1.18-1.11(m, 1H), 1.05-0.96 (m, 2H), 0.78-0.68 (m, 4H)

EXAMPLE 32N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide

Example 32 was prepared in analogy to the synthesis described forexample 31, using intermediate B3 instead of intermediate B2 andrequiring an additional HPLC purification. Yield: 35%

¹H NMR (DMSO-d₆): δ=8.99 (p, 1H), 8.90 (d, 1H), 8.76 (q, 1H), 8.54 (q,1H), 7.88-7.81 (m, 2H), 7.43-7.36 (m, 2H), 7.36-7.26 (m, 4H), 7.23-7.17(m, 1H), 5.79 (s, 1H), 3.95 (dd, 1H), 1.72-1.64 (m, 1H), 1.25-1.12 (m,2H), 1.04-0.91 (m, 2H), 0.81-0.66 (m, 4H)

EXAMPLE 33N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide

Example 33 was prepared in analogy to the synthesis described forexample 31, using intermediate B4 instead of intermediate B2. Yield: 32%

¹H NMR (DMSO-d₆): δ=8.91 (d, 1H), 8.62 (d, 1H), 8.39-8.34 (m, 2H),7.84-7.77 (m, 2H), 7.47-7.40 (m, 2H), 7.40-7.34 (m, 2H), 7.32 (t, 2H),7.22 (t, 1H), 5.80 (d, 1H), 3.98-3.94 (m, 1H), 1.72-1.62 (m, 1H),1.26-1.14 (m, 2H), 1.05-0.96 (m, 2H), 0.83-0.75 (m, 1H), 0.75-0.65 (m,3H)

EXAMPLE 34AN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)methanesulfonamide

Step 1:

(4S,5R)-4-Amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin-2-one(50.0 mg, 0.121 mmol, 1.0 eq.) was weighed out into a vial under anitrogen atmosphere, followed by the addition of DCM (1.2 mL) andtriethylamine (0.067 mL, 0.483 mmol, 4.0 eq.). The mixture was thencooled to 0° C., then methanesulfonyl chloride (0.019 mL, 0.241 mmol,2.0 eq.) was added and the mixture was allowed to stir for 10 minutes atthat temperature. The reaction mixture was then diluted with sat. NaHCO₃solution and DCM. The mixture was then filtered through a hydrophobicfrit and the organic layer was evaporated to dryness under reducedpressure. The obtained residue was purified via LC to yield 59.4 mg(76%) ofN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)methanesulfonamide.

¹H NMR (DMSO-d₆): δ=8.28 (d, 1H), 8.02 (d, 1H), 7.76-7.69 (m, 3H),7.69-7.63 (m, 1H), 7.52-7.47 (m, 2H), 7.44-7.35 (m, 3H), 7.29 (dd, 2H),7.23-7.18 (m, 1H), 5.07 (d, 1H), 3.70 (t, 1H), 2.03 (s, 3H), 1.26 (s,3H), 1.14 (s, 3H)

The examples in the following table were synthesized in analogy toExample 34a described above, using different intermediates. Theindividual reaction times vary.

Interme- Ex. diate Yield # (INT) Structure (%) ¹H NMR 34a Int A7 ent 2

52 ¹H NMR (DMSO-d₆): δ = 8.28 (d, 1H), 8.02 (d, 1H), 7.76-7.69 (m, 3H),7.69-7.63 (m, 1H), 7.52- 7.47 (m, 2H), 7.44-7.35 (m, 3H), 7.29 (dd, 2H),7.23-7.18 (m, 1H), 5.07 (d, 1H), 3.70 (t, 1H), 2.03 (s, 3H), 1.26 (s,3H), 1.14 (s, 3H) 35a Int A7 ent 1

13 ¹H NMR (DMSO-d₆): δ = 8.28 (d, 1H), 7.95 (d, 1H), 7.76-7.68 (m, 3H),7.65 (dd, 1H), 7.49-7.44 (m, 2H), 7.43-7.35 (m, 3H), 7.26 (t, 2H),7.20-7.14 (m, 1H), 5.09 (d, 1H), 3.74 (t, 1H), 1.46 (tt, 1H), 1.28 (s,3H), 1.15 (s, 3H), 0.70- 0.49 (m, 2H), 0.49-0.25 (m, 2H) 35b Int A7 ent2

8 ¹H NMR (DMSO-d₆): δ = 8.28 (d, 1H), 7.95 (d, 1H), 7.76-7.68 (m, 3H),7.65 (dd, 1H), 7.49-7.44 (m, 2H), 7.43-7.35 (m, 3H), 7.26 (t, 2H),7.20-7.14 (m, 1H), 5.09 (d, 1H), 3.74 (t, 1H), 1.46 (tt, 1H), 1.28 (s,3H), 1.15 (s, 3H), 0.70- 0.49 (m, 2H), 0.49-0.25 (m, 2H) 61 A9

74 ¹H NMR (DMSO-d₆) δ: 8.28 (d, 1H), 7.99 (d, 1H), 7.76-7.69 (m, 3H),7.65 (dt, 1H), 7.48-7.42 (m, 3H), 7.42-7.35 (m, 2H), 7.30- 7.25 (m, 2H),7.22-7.17 (m, 1H), 5.10 (d, 1H), 3.61 (dt, 1H), 2.68 (dq, 1H), 2.26 (s,3H), 1.31 (d, 3H) 62 A11- trans

50 ¹H NMR (DMSO-d₆) δ: 8.29 (s, 1H), 7.96 (d, 1H), 7.77-7.71 (m, 3H),7.69-7.64 (m, 1H), 7.44 (dd, 1H), 7.44-7.36 (m, 2H), 7.27 (d, 1H),7.25-7.21 (m, 1H), 7.16 (t, 1H), 7.01 (d, 1H), 5.05 (d, 1H), 3.58 (dt,1H), 2.67 (dq, 1H), 2.26 (s, 3H), 2.22 (s, 3H), 1.31 (d, 3H) 76 A11- cis

40 ¹H NMR (DMSO-d₆) δ: 7.89 (dd, 1H), 7.79-7.68 (m, 5H), 7.44- 7.37 (m,2H), 7.24 (t, 1H), 7.19 (d, 1H), 7.17-7.13 (m, 1H), 7.08 (ddd, 1H), 5.24(d, 1H), 3.97 (d, 1H), 3.01 (p, 1H), 2.87 (s, 3H), 2.27 (s, 3H), 1.18(d, 3H) 86 A13- cis

35 ¹H NMR (DMSO-d₆) δ: 8.35 (d, 1H), 8.19 (d, 0H), 7.87 (dd, 1H),7.80-7.73 (m, 3H), 7.65 (dd, 1H), 7.54-7.48 (m, 1H), 7.44-7.37 (m, 2H),7.37-7.28 (m, 3H), 5.58 (d, 1H), 4.09 (s, 1H), 3.04 (p, 1H), 2.95 (s,3H), 1.20 (d, 3H) 91 A21

42 ¹H NMR (DMSO-d₆) δ: 8.40 (d, 1H), 7.87-7.76 (m, 4H), 7.72 (d, 1H),7.45 (ddd, 3H), 7.40-7.33 (m, 4H), 7.26 (tt, 1H), 4.07 (td, 1H), 3.62(ddd, 1H), 3.15 (dd, 1H), 3.09 (dd, 1H), 2.96 (q, 1H), 2.79 (s, 3H),1.51 (ddd, 1H), 1.22 (dp, 1H), 0.40 (t, 3H) 93 A13- trans

19 ¹H NMR (Chloroform-d₃) δ: 8.10 (d, 1H), 7.68 (dd, 1H), 7.64-7.58 (m,2H), 7.55 (dd, 1H), 7.38 (dd, 2H), 7.31 (d, 1H), 7.26-7.18 (m, 4H), 5.68(s, 1H), 4.79 (d, 1H), 2.72 (dq, 1H), 2.51 (s, 3H), 1.55 (d, 3H),0.97-0.77 (m, 1H) 99 A15- trans

13 ¹H NMR (DMSO-d₆) δ: 8.28 (d, 1H), 7.93 (d, 1H), 7.75-7.72 (m, 2H),7.71 (dd, 1H), 7.65 (dt, 1H), 7.43-7.34 (m, 5H), 6.85-6.79 (m, 2H), 5.03(d, 1H), 3.65 (s, 3H), 3.59 (dt, 1H), 2.65 (dt, 1H), 2.29 (s, 3H), 1.31(d, 3H) 114 A17- trans

25 ¹H NMR (DMSO-d₆) δ: 8.34 (d, 1H), 7.98 (d, 1H), 7.81-7.74 (m, 3H),7.72 (dt, 1H), 7.47-7.38 (m, 3H), 7.14 (d, 1H), 6.89 (d, 1H), 5.34 (d,1H), 3.68 (dt, 1H), 2.70 (dq, 1H), 2.64 (s, 3H), 1.31 (d, 3H) 122 A19

47 ¹H NMR (DMSO-d₆) δ: 8.31 (t, 1H), 7.92 (d, 1H), 7.79-7.73 (m, 2H),7.72 (dd, 1H), 7.69 (dd, 1H), 7.52 (d, 1H), 7.45-7.37 (m, 3H), 6.27 (dd,1H), 5.11 (d, 1H), 3.79 (q, 1H), 3.70 (s, 3H), 2.67 2.59 (m, 1H), 2.46(s, 3H), 1.30 (d, 3H)

EXAMPLES 95 AND 96(2-(((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)carbamoyl)cyclopropan-1-ylium(example 95) andN-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(example 96)

Step-1:

In a dried vessel, intermediate C1-ent 1 (150 mg, 0.33 mmol) wasdissolved in dry THF (3.3 ml) under inert atmosphere. The solution wascooled down to −78° C. and a solution of LDA (1 M in THF/heptanes/ethylbenzene, 1.32 ml, 4.0 eq.) was added dropwise. After stirring for 15 minat −78° C., N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 229 mg,0.726 mmol, 2.2 eq.) dissolved in dry THF (1.7 mL) was added dropwise.The mixture was stirred for two hours at −78° C. before additionalamounts of LDA (330 1, 1 eq.) and NFSI (100 mg, 1 eq.) were addedsubsequently. After stirring for another 30 min at −78° C., the reactionwas quenched with sat. NH₄Cl-solution and ethyl acetate was added afterstirring for 5 minutes. The layers were separated, the organic layer wasdried over sodium sulfate and the solvent was removed in vacuo. Thecrude material was purified via flash chromatography (silica,cyclohexane/ethyl acetate gradient as eluent) and subsequent prep.-HPLC(water/acetonitrile gradient) to obtain example 95 (25.5 mg, 0.054 mmol,16%) and example 96 (3.0 mg, 0.006 mmol, 2%) as white solids.

EXAMPLE 95

¹H NMR (Chloroform-d₃) δ: 8.07 (d, 1H), 7.76 (dd, 0.7 Hz, 1H), 7.67-7.50(m, 2H), 7.58-7.45 (m, 1H), 7.39 (dd, 1H), 7.41-7.06 (m, 6H), 6.31 (d,1H), 5.86 (dd, 1H), 5.54 (dd, 1H), 3.98 (dq, 1H), 1.44 (tt, 1H), 0.86(dtd, 2H).

EXAMPLE 96

¹H NMR (Chloroform-d₃) δ: 8.10 (s, 1H), 7.52 (d, 1H), 7.41 (dd, 1H),7.43-7.19 (m, 5H), 7.28-7.11 (m, 2H), 6.42 (s, 1H), 5.14 (d, 1H), 4.88(dddd, 1H), 1.51 (tq, 1H), 1.05 (tq, 1H), 0.96-0.74 (m, 2H).

EXAMPLE 1002,2-difluoro-N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)propanamide

Step 1:

To a stirred solution of intermediate A6 (1 g, 3.08 mmol, 1.0 eq) inmethanol (30 mL), Pd—C(820 g, 10%, moist) was added and the reaction wasstirred with hydrogen balloon for 2 h at RT. After completion,(monitored by TLC, TLC system 5% MeOH in DCM, R_(f)-0.2), the reactionmixture was filtered through celite bed and washed 2-3 times with MeOH.The filtrate was concentrated to get the desiredtrans-4-amino-5-methyl-5-phenylpyrrolidin-2-one as off-white solid(0.693 g, 94%).

Step 2:

To a stirred solution of 2,2-difluoropropanoic acid (0.304 g, 2.759mmol, 1.5 eq) in DMF (10 mL), DIPEA (1.6 mL 9.14 mmol, 5.0 eq), HATU(1.4 g, 3.678 mmol, 2.0 eq), andtrans-4-amino-5-methyl-5-phenylpyrrolidin-2-one (350 mg, 1.839 mmol, 1eq) was added at ice cold condition and the reaction was stirred at RTfor 16 h. After completion of the reaction, (monitored by TLC, TLCsystem 5% MeOH in DCM, R_(f)-0.3), the reaction mixture was diluted withEtOAc (20 mL) and washed with ice cold water (3×25 mL), dried overNa₂SO₄ and concentrated to get the crude product which was purified bycolumn chromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) toafford2,2-difluoro-N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)propanamide(0.350 g, 67%).

Step 3:

A stirred solution of2,2-difluoro-N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)propanamide(0.250 g, 0.885 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole(0.359 g, 1.0627 mmol, 1.2 eq), K₃PO₄ (0.376 g, 1.770 mmol, 2 eq) in 1,4dioxane (10 mL) was degassed with argon for 30 min.N,N′-dimethylethylenediamine (0.032 g, 0.354 mmol, 0.4 eq) and CuI(0.033 g, 0.177 mmol, 0.2 eq) was added and the reaction mixture wasstirred for 72 h at 90° C. in a sealed tube. After completion of thereaction, (monitored by TLC, TLC system 5% MeOH in DCM, R_(f)-0.4), thereaction mixture was filtered through celite bed and washed 2-3 timeswith dioxane. The combined organic layer was concentrated to get thecrude product which was purified by column chromatography (230-400 meshsilica gel; 0 to 2% MeOH in DCM) to afford2,2-difluoro-N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)propanamide(0.046 g, 11%) as off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (d, J=8.84 Hz, 1H), 8.32 (s, 1H),7.78-7.73 (m, 3H), 7.49-7.30 (m, 9H), 4.53-4.49 (m, 1H), 3.00-2.93 (m,1H), 2.47-2.42 (m, 1H), 1.78 (t, J=19.52 Hz, 3H), 1.44 (s, 3H).

EXAMPLE 101N-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

Step 1:

To a stirred solution of trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one(350 mg, 1.84 mmol, 1 eq) in DMF (10 mL) TEA (1.2 mL, 9.14 mmol, 5.0eq), cyclopropanecarbonyl chloride (288 mg, 2.76 mmol, 1.5 eq) was addedat ice cold condition and the reaction mixture was stirred at RT for 2h. After completion of the reaction, (monitored by TLC, TLC system 5%MeOH in DCM, R_(f)-0.3), the reaction mixture was diluted with EtOAc (50mL) and washed with ice cold water (3×25 mL), dried over Na₂SO₄ andconcentrated to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) to affordN-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(350 mg, 74%).

Step 2:

A stirred solution ofN-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(0.250 g, 0.967 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole(0.393 g, 1.16 mmol, 1.2 eq), K₃PO₄ (0.410 g, 1.93 mmol, 2 eq) in 1,4dioxane (10 mL) was degassed with argon for 30 min.N,N′-dimethylethylenediamine (0.034 g, 0.387 mmol, 0.4 eq) and CuI(0.037 g, 0.193 mmol, 0.2 eq) was added and the reaction mixture wasstirred for 72 h at 90° C. in a sealed tube. After completion of thereaction, (monitored by TLC, TLC system 5% MeOH in DCM, R_(f)-0.4), thereaction mixture was filtered through celite bed and washed 2-3 timeswith dioxane. The combined organic layer was concentrated to get thecrude product which was purified by column chromatography (230-400 meshsilica gel; 0 to 2% MeOH in DCM) to affordN-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(0.046 g, 10%) as off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=8.88 Hz, 1H), 8.35 (s, 1H),7.79-7.74 (m, 3H), 7.52 (s, 1H), 7.48-7.32 (m, 8H), 4.50-4.45 (m, 1H),2.91-2.85 (m, 1H), 2.30-2.26 (m, 1H), 1.66-1.63 (m, 1H), 1.44 (s, 3H),0.69 (d, J=6.2 Hz, 4H).

EXAMPLE 121N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

Synthesis of methyl 3-cyclopropyl-2-(nitromethyl)propanoate. To astirred solution of methyl 3-nitropropanoate (15 g, 112.74 mmol) in THF(105 ml) was added LDA (2M in THF, 112.7 ml, 225.5 mmol) at −78° C. andthe resulting solution was stirred for 1 h at the same temperature.(Bromomethyl)cyclopropane (21.28 ml, 225.5 mmol) was added at −78 C. Thereaction mixture was gradually allowed to reach rt and stirring wascontinued for 16 h. The reaction mixture was quenched with aqueous NH₄Clat 0° C. The layers were separated and the aqueous part was extractedwith ethyl acetate (600 ml×3). The combined organic layers were washedwith brine (300 ml), dried over Na₂SO₄ and concentrated. The crudeproduct was purified by column chromatography (using 100-200 mesh silicagel, 6-8% ethyl acetate-hexanes as eluent) to afford3-cyclopropyl-2-(nitromethyl)propanoate as brown oil.

Step-2:

Synthesis ofrac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenylpyrrolidin-2-one.To a stirred solution of benzaldehyde (6.07 ml, 60.09 mmol) in toluene(112.5 ml) was added 4-methoxy benzylamine (8.24 g, 60.09 mmol) at rtand stirred for 2 h. methyl 3-cyclopropyl-2-(nitromethyl)propanoate (7.5g, 40.06 mmol) was added to the reaction mixture followed by benzoicacid (7.34 g, 60.09 mmol) and the resulting mixture was stirred for 7-8h at 70° C. After completion of the reaction (monitored by LCMS), themixture was diluted with ethyl acetate (300 ml) and washed with water(200 ml), followed by sat.NaHCO₃ (100 ml×2). The organic layer was driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedby column chromatography (using silica gel 100-200 mesh; 12-15% ethylacetate in hexanes as eluent) to afford 4rac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenylpyrrolidin-2-one(7.5 g, 49.1%) as brown oil.

Step-3:

rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one.To a stirred solution ofrac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenylpyrrolidin-2-one(6 g, 15.77 mmol) in acetonitrile (120 ml) was dropwise added a solutionof CAN (25.93 g, 47.31 mmol) in water (120 ml) at 0° C. The reactionmixture was slowly warmed to 10-15° C. and stirring was continued for3-4 h. After completion of the reaction (monitored by TLC, 30% ethylacetate/hexane, Rf 0.3), the mixture was diluted with ethyl acetate (400ml) and washed with water (200 ml) followed by brine (200 ml). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude materialwas purified by column chromatography (using silica gel 100-200 mesh;25-30% ethyl acetate in hexane as eluent) to affordrac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one(3.51 g, 85.6%) as a colorless oil.

Step-4:

rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one.To a stirred solution ofrac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one (4g, 15.36 mmol) in ethyl acetate-methanol (360 ml, 2:1) was added 6 N aq.HCl (118 ml) at 0° C. Zinc dust (60.29 g, 922.04 mmol) was addedportionwise at the same temperature. The resulting suspension wasstirred at room temperature for 16 h. After completion of the reaction(monitored by LCMS), it was quenched with saturated NaHCO₃ solution at0° C., stirred for 1 h, filtered over celite and washed with ethylacetate-methanol (500 ml, 2:1). The filtrate was concentrated to affordrac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one(3.53 g crude, considered as 100% yield) as off white solid which wasused in next step without further purification.

Step-5:

Synthesis of tert-butyl(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)carbamate.To a stirred suspension ofrac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one(3.53 g crude, 15.34 mmol) in THF-Water (1:1, 400 ml) was added sodiumbicarbonate (3.86 g, 46.04 mmol) at 0° C. and the resulting mixture wasstirred for 30 minutes at the same temperature. Di-tert-butyldicarbonate (10.6 ml, 46.04 mmol) was added to the reaction mixture at0° C. and stirring was continued for 16 h at rt. After completion of thereaction (monitored by LCMS), the mixture was diluted with water (200ml) and extracted with ethyl acetate (3×300 ml). The combined organiclayers were washed with water (300 ml) followed by brine (300 ml). Afterdrying over Na₂SO₄ and concentrating, the crude material was purified bycolumn chromatography (using silica gel 100-200 mesh; 1.5-2% MeOH in DCMas eluent) to afford(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)carbamate(3.52 g, 69.5%) as off white solid.

Step-6:

Synthesis is ofrac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-onehydrochloride. To a stirred suspension of(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)carbamate(2 g, 6.05 mmol) in 1,4-dioxane (10 ml) was added 4 N HCl in 1,4-dioxaneat 0° C. and stirring was continued at rt for 16 h. After completion ofthe reaction (monitored by LCMS), the mixture was concentrated andtrituated with ether to affordrac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-onehydrochloride (1.62 g, crude) as off white solid.

Step-7:

Synthesis ofN-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide.To a stirred solution of4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one hydrochloride (7)(1.62 g, 6.06 mmol) in DCM (30 ml) was added Et₃N (2.54 ml, 18.21 mmol)at 0° C. and the resulting mixture was stirred at the same temperaturefor 20 minutes. A solution of cyclopropanecarbonyl chloride (0.56 ml,6.06 mmol) in DCM (5 ml) was added and stirring was continued at 0°C.-10° C. for 3 h. After complete consumption of the starting material(monitored by LCMS), the reaction was diluted with H₂O, the formedprecipitate was filtered and washed with cold water followed bypentane-ether to affordN-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(1.41 g, 78%) as off white solid.

Step-8:

C—N-coupling was performed in analogy to the procedure described forexample 7 Step 1 usingN-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide.Yield 53%.

¹H NMR (DMSO-d₆) δ: 8.59 (d, 1H), 8.29 (s, 1H), 7.79 (d, 1H), 7.77-7.70(m, 2H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.43-7.36 (m, 2H), 7.32 (d, 2H),7.25 (t, 2H), 7.19-7.13 (m, 1H), 5.21 (d, 1H), 4.33 (q, 1H), 2.83 (dt,1H), 1.67-1.59 (m, 2H), 1.57 (ddd, 1H), 0.90 (ddt, 1H), 0.73-0.60 (m,4H), 0.50-0.32 (m, 2H), 0.18-0.01 (m, 2H)

EXAMPLE 127N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide,diastereomer 2; and EXAMPLE 130N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide,diastereomer 1

In a dried vessel, intermediate C1—ent 1 (150 mg, 0.33 mmol) wasdissolved in dry THF (3.3 ml) under inert atmosphere. The solution wascooled down to −78° C. and a solution of freshly prepared LDA (1 M inTHF, 0.825 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at−78° C., (2-Iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.) dissolvedin dry THF (1.7 mL) was added dropwise. The mixture was allowed to warmup to −20° overnight and cooled down again to −60° C. before additional(2-Iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.) and LDA (1 M in THF,0.682 ml, 2.0 eq.) were added. After stirring for 90 minutes at −60° C.,a third amount of (2-Iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.)followed by LDA (1 M in THF, 0.34 ml, 1.0 eq.). The mixture was stirredagain overnight at −20° C. and quenched with saturated NH₄Cl solution atthat temperature before the mixture was diluted with ethyl acetate. Thecrude material was purified via flash chromatography (silica,cyclohexane/ethyl acetate gradient as eluent) and subsequent prep.-HPLC(water/acetonitrile gradient) to obtain example 127(N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamidesecond eluting diastereomer, 6 mg, 0.011 mmol, 3%) and example 130(N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamidefirst eluting diastereomer, 12.0 mg, 0.021 mmol, 6%) as white solids.

EXAMPLE 127

¹H NMR (DMSO-d₆) δ: 8.94 (d, 1H), 8.35-8.28 (m, 1H), 8.01 (d, 1H), 7.83(dd, 1H), 7.80-7.63 (m, 3H), 7.44-7.23 (m, 9H), 7.26-7.16 (m, 1H),7.19-7.13 (m, 2H), 7.15-7.03 (m, 1H), 5.26 (d, 1H), 4.52 (ddd, 1H), 2.93(tdd, 1H), 2.65-2.52 (m, 2H), 1.85-1.68 (m, 2H), 1.24 (s, 1H), 1.18 (s,1H), 0.90-0.69 (m, 3H).

EXAMPLE 128

¹H NMR (DMSO-d₆) δ: 8.66 (d, J=8.4 Hz, 1H), 8.29 (d, J=1.3 Hz, 1H), 7.79(d, J=1.9 Hz, 1H), 7.74 (ddd, 2H), 7.68 (d, 1H), 7.54-7.48 (m, 1H),7.43-7.36 (m, 2H), 7.36-7.28 (m, 4H), 7.26 (t, 2H), 7.23-7.14 (m, 4H),5.21 (d, 1H), 4.22 (td, 1H), 2.76 (t, 2H), 2.70 (td, 1H), 2.18 2.06 (m,2H), 1.88 (dq, 1H), 1.58 (tt, 1H), 0.77-0.62 (m, 4H).

EXAMPLES 128N-(rac-(2R,3R,4R)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamideand example 129N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

In a 250 ml round-bottom-flask, a solution of intermediate A8 (2370 mg,7.31 mmol) in acetonitrile (120 ml) was added to sodium iodide (6570 mg,43.8 mmol, 6 eq.) under nitrogen atmosphere. To the resulting mixture,trimethylsilyl chloride (3.71 ml, 29.2 mmol 4.0 eq.) was added dropwise.After stirring overnight at room temperature, the reaction mixture wasadded dropwise to ethanol (142 ml) and filtered over celite. Thefiltrate was loaded on a strong cation exchange-cartridge (SCX, 5 g),flushed two times with ethanol (15 ml each) and eluated with 2 M NH₃ inmethanol (2×10 mL). This procedure was repeated using theproduct-containing fractions two times. The clean fractions werecombined, and the solvent was removed in vacuo to obtainrac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (296 mg, 1.56mmol, 21%) as a colorless resin.

Step-2:

rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (328 mg, 1.72mmol) and cyclopropanecarboxylic acid (297 mg, 3.45 mmol, 2.0 eq.) weredissolved in dichloromethane (17.2 ml) at room temperature.Triethylamine (689 mg, 6.90 mmol, 4.0 eq.) was added dropwise to themixture which was stirred until all starting materials had dissolved.Propylphosphonic anhydride solution (>50 wt. % in ethyl acetate, 2.57ml, 4.31 mmol, 2.5 eq.) was added to the reaction and stirring wascontinued at rt. After 3 h, reaction control (UPLC) showed fullconsumption of the starting materials and the reaction was quenched with1 M Na₂CO₃-solution. After stirring for one hour, the productprecipitated and was filtered off yieldingN-(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(264 mg, 1.02 mmol, 59%) as a white solid. The obtained material wasused in the next step without further purification.

Step-3:

To a suspension ofN-(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(263 mg, 1.02 mmol), triethyl amine (206 mg, 2.04 mmol, 2.0 eq.) and4-dimethylamino pyridine (12.4 mg, 0.102 mmol, 0.1 eq.) in acetonitrile(10 ml), a solution of di-tert-butyl-dicarbonate (244 mg, 1.12 mmol, 1.1eq.) in acetonitrile (2 ml) was added in a sealed tube. The reactionmixture was heated to 80° C. for 30 minutes and stirred overnight atroom temperature. Additional di-tert-butyl-dicarbonate (133 mg, 0.611mmol, 0.6 eq.) in acetonitrile (2 ml) was added and stirring wascontinued at room temperature until reaction control (UPLC) proved thereaction to be complete (2 h). Dichloromethane and saturatedNaHCO₃-solution were added to the reaction, the layers were separatedand the aqueous layer was extracted once with dichloromethane. Thecombined organic layers were dried over magnesium sulfate and thesolvent was removed in vacuo. The crude material was purified via flashchromatography (12 g silica, cyclohexane/ethyl acetate gradient aseluent) and tert-butylrac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3-methyl-2-oxo-5-phenyl-pyrrolidine-1-carboxylate(234 mg, 0.653 mmol, 64%) was obtained as a white solid.

Step-4:

In a dried vessel, tert-butylrac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3-methyl-2-oxo-5-phenyl-pyrrolidine-1-carboxylate(80 mg, 0.223 mmol) was dissolved in dry THF (2.2 ml) under inertatmosphere. The solution was cooled down to −78° C. and a solution oflithium bis(trimethylsilyl)amide (1 M in THF, 0.446 ml, 0, 446 mmol, 2.0eq) was added carefully. After stirring for 15 minutes at −78, asolution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (70.4 mg,0.223 mmol, 1.0 eq) in THF (1 mL) was added dropwise. After stirring for45 min at that temperature, another amount ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (35.0 mg, 0.111 mmol, 0.5eq.) in THF (0.5 mL) were added and stirring was continued for 30 min.The reaction was quenched at −78° using sat. NH₄Cl solution, dilutedwith DCM and quickly poured over a hydrophobic frit, before the mixturecould warm up. The organic layer was washed with water and separatedagain. The crude product was purified via flash chromatography (12 gsilica, cyclohexane/ethyl acetate gradient as eluent) to yieldtert-butyl(4R,5R)-4-(cyclopropanecarboxamido)-3-fluoro-3-methyl-2-oxo-5-phenylpyrrolidine-1-carboxylate(47 mg, 0.125 mmol, 56%) as a mixture of epimers (3:1).

Step-5:

To a solution of tert-butyl(4R,5R)-4-(cyclopropanecarboxamido)-3-fluoro-3-methyl-2-oxo-5-phenylpyrrolidine-1-carboxylate(46.0 mg, 0.122 mmol) in dichloromethane (1.22 ml) was addedtrifluoroacetic acid (0.094 ml, 1.22 mmol, 10.0 eq.) at roomtemperature. After stirring for 30 minutes, reaction control (UPLC)proved the reaction to be complete and the mixture was quenched usingsat. NaHCO₃-solution. DCM was added to the mixture and layers wereseparated by the means of a hydrophobic frit. Evaporation of the organiclayer gaveN-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(27 mg, 0.098 mmol, 80%) as a brown oil which was used without furtherpurification

Step-6:

In a sealed tube,N-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(27.0 mg, 0.098 mmol), 1-(4-fluorophenyl)-5-iodo-indazole (36.3 mg,0.107 mmol, 1.1 eq.), K₃PO₄ (41.5 mg, 0.195 mmol, 2.0 eq) and CuI (3.7mg, 0.020 mmol, 0.2 eq.) were dissolved in degassed 1,4-dioxane (1 ml).To the mixture, (1R,2R)—N,N′-dimethyl-1,2-cyclohexandiamine (5.6 mg,0.039 mmol, 0.4 eq.) was added and the reaction was heated to 100° C.overnight and to 120° C. for 5 h. The reaction was quenched using sat.NaHCO₃-solution and diluted with dichloromethane. The layers wereseparated by the means of a hydrophobic frit and the aqueous layer waswashed multiple times with DCM. The organic layers were combined and thesolvent was evaporated. The crude material was purified via flashchromatography (silica, cyclohexane/ethyl acetate gradient as eluent)and subsequent prep.-HPLC (water/acetonitrile gradient) to obtainexample 128N-((2R,3R,4R)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(1.8 mg, 0.003 mmol, 4%) and example 129N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(5.8 mg, 0.012 mmol, 12%).

EXAMPLE 128

¹H NMR (DMSO-d₆) δ:8.11 (d, 1H), 7.78 (dd, 1H), 7.67-7.59 (m, 2H), 7.56(dt, 1H), 7.48 (dd, 1H), 7.39-7.19 (m, 6H), 7.26-7.16 (m, 1H), 6.29-6.20(m, 1H), 5.15 (d, 1H), 4.66 (ddd, 1H), 1.69 (d, 3H), 1.47 (tt, 1H), 1.01(dddd, 1H), 0.95-0.90 (m, 1H), 0.82 (m, 2H).

EXAMPLE 129

¹H NMR (DMSO-d₆) δ: 8.69 (dd, 1H), 8.33 (d, 1H), 7.87 (d, 1H), 7.82-7.67(m, 3H), 7.51 (dd, 1H), 7.45-7.30 (m, 4H), 7.26 (t, 2H), 7.22-7.13 (m,1H), 5.12 (dd, 1H), 4.68 (ddd, 1H), 1.66 (tt, 1H), 1.54 (d, 3H),0.77-0.65 (m, 3H), 0.58 (dtd, 1H)

EXAMPLE 131N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamideand example 132N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

In a dried vessel, intermediate C1—ent 1 (150 mg, 0.33 mmol) wasdissolved in dry THF (3.3 ml) under inert atmosphere. The solution wascooled down to −78° C. and a solution of freshly prepared LDA (1 M inTHF, 0.825 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at−78° C., 1,1-difluoro-2-iodo-ethane (82.4 mg, 0.429 mmol, 1.3 eq.)dissolved in dry THF (1.7 mL) was added dropwise. The mixture was warmedup to −40° C. and stirred overnight at that temperature. Another amountof, 1,1-difluoro-2-iodo-ethane (82.4 mg, 0.429 mmol, 1.3 eq.) was addedand the mixture was warmed up to −20° C. At this temperature, sat.NH₄Cl-solution was added and stirring was continued before the mixturewas diluted with ethyl acetate. After the layers were separated, theorganics were dried over sodium sulfate and the solvent was removed invacuo. The crude material was purified via flash chromatography (12 gsilica, cyclohexane/ethyl acetate gradient as eluent) to obtain example131N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(9.0 mg, 0.017 mmol, 5%) and example 132N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(7.0 mg, 0.014 mmol, 4%) as white solids.

EXAMPLE 131

¹H NMR (DMSO-d₆) δ: 8.30 (d, J=1.0 Hz, 1H), 7.85-7.64 (m, 3H), 7.68 (d,1H), 7.56-7.21 (m, 6H), 7.36-7.07 (m, 3H), 5.24 (d, 1H), 4.25 (q, 1H),2.97 (q, 1H), 2.54-2.34 (m, 1H), 1.25 (s, 2H), 0.81-0.52 (m, 3H).

EXAMPLE 132

¹H NMR (DMSO-d₆) δ: 8.95 (d, 1H), 8.33 (s, 1H), 8.02 (d, 1H), 7.85 (dd,J=9.2, 2.1 Hz, 1H), 7.87-7.67 (m, 3H), 7.51-7.19 (m, 7H), 5.28 (s, 1H),4.42 (t, 1H), 3.22-3.02 (m, 1H), 2.25-2.02 (m, 1H), 1.24 (s, 2H),0.96-0.63 (m, 4H).

EXAMPLE 134N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

In a dried vessel, example 46 (50 mg, 0.107 mmol) was dissolved in dryTHF (1.1 ml) under inert atmosphere. The solution was cooled down to−78° C. and a solution of freshly prepared LDA (1 M in THF, 0.267 ml,2.5 eq.) was added dropwise. After stirring for 15 min at −78° C.,iodoethane (25.0 mg, 0.160 mmol, 1.5 eq.) dissolved in dry THF (0.5 mL)was added dropwise. The mixture was warmed up to −60° C. and stirred for90 minutes at that temperature. Then, the reaction was cooled down againto −78° C. before another amount of Iodoethane (12.5 mg, 0.080 mmol,0.75 eq.) dissolved in dry THF (0.5 ml) was added. After stirring for 1h at −78° C. the reaction was quenched with saturated NH₄Cl-solution anddiluted with dichloromethane after stirring for 5 min. The layers wereseparated by the means of a hydrophobic frit. The organic layer waswashed with water, separated again and dried over sodium sulfate. Afterremoval of the solvent, the crude material was purified via flashchromatography (silica, cyclohexane/ethyl acetate gradient as eluent)and subsequent prep.-HPLC (water/acetonitrile gradient) to obtainexample 134N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(6 mg, 0.012 mmol, 11%) as a colorless resign.

¹H NMR (DMSO-d₆) δ 8.47 (d, 1H), 8.30 (d, 1H), 7.77-7.71 (m, 3H), 7.68(d, 1H), 7.46 (dd, 1H), 7.39 (dd, 2H), 7.36-7.33 (m, 2H), 7.24 (t, 2H),7.15 (td, 1H), 5.15 (d, 1H), 4.33 (t, 1H), 1.72-1.63 (m, 2H), 1.54 (dq,1H), 1.24 (s, 3H), 0.95 (d, 2H), 0.73-0.67 (m, 1H), 0.63 (qt, 2H),0.59-0.50 (m, 1H).

EXAMPLE 135N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspiro[3.4]octan-8-yl)cyclopropanecarboxamid

In a dried vessel, intermediate C1—ent 1 (150 mg, 0.33 mmol) wasdissolved in dry THF (3.3 ml) under inert atmosphere. The solution wascooled down to −78° C. and a solution of freshly prepared LDA (1 M inTHF, 0.825 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at−78° C., 1,3-Dibromopropane (93.3 mg, 0.462 mmol, 1.3 eq.) dissolved indry THF (1.7 mL) was added dropwise. The mixture was warmed up to roomtemperature overnight. The mixture was cooled down again to −20° C.before additional amounts of LDA (1 M in THF, 0.330 ml, 1.0 eq.) and1,3-dibromopropane (71.8 mg, 0.355 mmol, 1.0 eq.) were added. Afterstirring for 15 minutes, another amount of LDA (1 M in THF, 0.495 ml,1.5 eq.) was added. The mixture was allowed to warm up to roomtemperature again overnight and quenched with sat. NH₄Cl-solution.Stirring was continued for 5 minutes before the mixture was diluted withethyl acetate. After the layers were separated, the organics were driedover sodium sulfate and the solvent was removed in vacuo. The crudematerial was purified via flash chromatography (12 g silica,cyclohexane/ethyl acetate gradient as eluent) to obtain example 135N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspiro[3.4]octan-8-yl)cyclopropanecarboxamid(11 mg, 0.022 mmol, 7%) colorless resin.

¹H NMR (DMSO-d₆) δ: 8.09 (d, 1H), 7.99 (dd, 1H), 7.81 (dd, 1H), 7.63(ddd, 2H), 7.56 (dt, 1H), 7.43-7.39 (m, 2H), 7.35-7.30 (m, 3H),7.28-7.24 (m, 1H), 7.24-7.20 (m, 2H), 6.03 (d, 1H).

EXAMPLE 137N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

In a dried vessel, example 106 (70 mg, 0.141 mmol) was dissolved in dryTHF (1.4 ml) under inert atmosphere. The solution was cooled down to−78° C. and a solution of freshly prepared LDA (1 M in THF, 0.352 ml,2.5 eq.) was added dropwise. After stirring for 15 min at −78° C.,N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 66.7 mg, 0.211mmol, 1.5 eq.) dissolved in dry THF (0.7 mL) was added dropwise. Themixture was stirred for 15 min at −78° C. and quenched with saturatedNH₄Cl-solution. After stirring for 5 min, the mixture was diluted withethyl acetate and the layers were separated. After removal of thesolvent, the crude material was purified via via flash chromatography(silica, cyclohexane/ethyl acetate gradient as eluent) to give example137N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(4 mg, 0.008 mmol, 6%) as a colorless oil.

¹H NMR (Chloroform-d₃) δ: 8.19 (d, 1H), 7.67 (dd, 3H), 7.57 (d, 1H),7.39-7.34 (m, 3H), 7.32 (dd, 2H), 7.28-7.25 (m, 2H), 7.22 (dd, 1H), 6.01(t, 1H), 4.97-4.86 (m, 1H), 3.51-3.42 (m, 1H), 3.34 (dd, 1H), 3.17-3.08(m, 1H), 1.54 (qd, 2H), 1.42 (tt, 1H), 1.15-1.09 (m, 1H), 1.10-1.05 (m,1H), 0.94-0.88 (m, 1H), 0.85 (dddd, 1H), 0.75 (t, 3H).

EXAMPLE 138N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide

Example 138 was prepared in analogy to the synthesis described forexample 131 using 5-(bromomethyl)-3-methyl-1,2,4-oxadiazole instead of1,1-difluoro-2-iodo-ethane. Yield: 9%

¹H NMR (DMSO-d₆) δ: 8.55 (d, 1H), 8.29 (d, 1H), 7.77-7.70 (m, 3H),7.70-7.64 (m, 1H), 7.47-7.36 (m, 5H), 7.24 (t, 2H), 7.17-7.10 (m, 1H),5.27 (d, 1H), 4.41 (q, 1H), 3.46-3.36 (m, 1H), 2.35 (s, 3H), 1.50 (tt,1H), 0.71-0.50 (m, 4H).

EXAMPLE 139AN-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-H-pyrazol-4-yl)methyl)-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamideand example 139bN-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide

Examples 139a and 139b were prepared in analogy to the synthesisdescribed for examples 131 and 132 using and 5.0 eq. of LDA and4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide instead of1,1-difluoro-2-iodo-ethane. Yields: 7% (139a) and 6% (139b).

EXAMPLE 139A

¹H NMR (Chloroform-d₃) δ: 8.06 (d, 1H), 7.68 (d, 1H), 7.61-7.54 (m, 2H),7.51-7.43 (m, 2H), 7.37 (dd, 1H), 7.29 (d, 1H), 7.25-7.13 (m, 5H),7.07-7.00 (m, 2H), 6.13 (d, 1H), 5.13 (d, 1H), 4.23 (dt, 1H), 3.87 (s,3H), 3.08-2.98 (m, 3H), 1.38 (tt, 1H), 1.05-0.93 (m, 2H), 0.79 (ddddd,2H).

EXAMPLE 139B

¹H NMR (Chloroform-d₃) δ: 8.07 (d, 1H), 7.95 (d, 1H), 7.69 (dd, 1H),7.64-7.58 (m, 2H), 7.51 (d, 1H), 7.42-7.33 (m, 5H), 7.32-7.27 (m, 1H),7.26 (s, 1H), 7.25-7.19 (m, 2H), 6.58 (d, 1H), 5.17 (s, 1H), 4.58 (t,1H), 3.84 (s, 3H), 3.21-3.11 (m, 2H), 2.92-2.83 (m, 1H), 1.50 (tt, 1H),1.16-1.07 (m, 2H), 0.94-0.81 (m, 2H).

EXAMPLE 148N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

In a dried vessel, example 46 (71 mg, 0.152 mmol) was dissolved in dryTHF (1.5 ml) under inert atmosphere. The solution was cooled down to−78° C. and a solution of freshly prepared LDA (1 M in THF, 0.379 ml,2.5 eq.) was added dropwise. After stirring for 15 min at −78° C.,1,1-difluoro-2-iodo-ethane (43.6 mg, 0.160 mmol, 1.5 eq.) dissolved indry THF (0.75 mL) was added dropwise. The mixture was warmed up to −50°C. and stirred for 45 minutes at that temperature. Then, another amountof 1,1-difluoro-2-iodo-ethane (11.4 mg, 0.110 mmol, 0.75 eq.) dissolvedin dry THF (0.5 ml) was added. After stirring for 1 h at −78° C. thereaction was quenched with saturated NH₄Cl-solution and diluted withdichloromethane after stirring for 5 min. The layers were separated bythe means of a hydrophobic frit. The organic layer was washed withwater, separated again and dried over sodium sulfate. After removal ofthe solvent, the crude material was purified via prep.-HPLC(water/acetonitrile gradient) to obtain example 148N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide 3.0 mg 0.0056 mmol, 3.7%) as a colorless resin.

¹H NMR (Chloroform-d₃) δ: 8.07 (d, 1H), 7.63 (d, 1H), 7.60-7.56 (m, 2H),7.50 (dt, 1H), 7.32 (dd, 1H), 7.29-7.25 (m, 4H), 7.23-7.18 (m, 3H), 6.43(tdd, 1H), 5.91 (dd, 1H), 4.92 (d, 1H), 4.78 (t, 1H), 2.50-2.39 (m, 1H),2.39-2.27 (m, 1H), 1.43-1.37 (m, 1H), 1.36 (s, 3H), 0.97 (dddd, 1H),0.86 (dddd, 1H), 0.83-0.77 (m, 1H), 0.74 (dddd, 1H).

EXAMPLE 149N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenlpyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

In a dried vessel, example 121 (150 mg, 0.295 mmol) was dissolved in dryTHF (3 ml) under inert atmosphere. The solution was cooled down to −78°C. and a solution of freshly prepared LDA (1 M in THF, 0.737 ml, 2.5eq.) was added dropwise. After stirring for 15 min at −78° C.,iodomethane (62.8 mg, 0.442 mmol, 1.5 eq.) was added dropwise. Themixture was stirred for 45 minutes at that temperature. Then, anotheramount of iodomethane (42 mg, 0.110 mmol, 1 eq.) was added. Afterstirring for 1 h at −78° C. the reaction was quenched with saturatedNH₄Cl-solution and diluted with dichloromethane after stirring for 5min. The layers were separated by the means of a hydrophobic frit. Theorganic layer was washed with water, separated again and dried oversodium sulfate. After removal of the solvent, the crude material waspurified via prep.-HPLC (water/acetonitrile gradient) to obtain Example149N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(14.0 mg, 0.0268 mmol, 9%) as a colorless resin.

¹H NMR (DMSO-d₆) δ: 8.44 (d, 1H), 8.30 (d, 1H), 7.79-7.70 (m, 3H), 7.68(d, 1H), 7.47 (dd, 1H), 7.43-7.33 (m, 4H), 7.23 (t, 2H), 7.15 (td, 1H),5.23 (d, 1H), 4.34 (t, 1H), 1.85 (dd, 1H), 1.69 (ddd, 1H), 1.30 (s, 3H),1.13 (dd, 1H), 1.05 (tt, 1H), 0.71 (tdd, 1H), 0.68-0.58 (m, 2H), 0.55(tdt, 1H), 0.45-0.36 (m, 2H), 0.08-0.05 (m, 2H).

EXAMPLE 150N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(thiazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

In a dried vessel, intermediate C1—ent 1 (150 mg, 0.295 mmol) wasdissolved in dry THF (4.7 ml) under inert atmosphere. The solution wascooled down to −78° C. and a solution of freshly prepared LDA (1 M inTHF, 1.32 ml, 4 eq.) was added dropwise. After stirring for 15 min at−78° C., 2-(chloromethyl)-1,3-thiazole hydrochloride (67 mg, 0.396 mmol,1.2 eq.) was added as a solid. The mixture was for one hour at −40° C.Then, another amount of LDA (1 M in THF, 0.165 ml, 1 eq.) followed by2-(chloromethyl)-1,3-thiazole hydrochloride (28.1 mg, 0.165 mmol, 0.5eq.) was added. After stirring overnight at −40° C., the reaction wasquenched with saturated NH₄Cl-solution and diluted with dichloromethaneafter stirring for 5 min. The layers were separated by the means of ahydrophobic frit. The organic layer was washed with water, separatedagain and dried over sodium sulfate. After removal of the solvent, thecrude material was purified via prep.-HPLC (water/acetonitrile gradient)to obtain example 150.N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(thiazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide(26.3 mg 0.0477 mmol 14%) as a off-white solid.

¹H NMR (600 MHz, Chloroform-d₃) δ: 9.22 (d, 1H), 8.06 (d, 1H), 7.77 (d,1H), 7.72 (d, 1H), 7.65-7.58 (m, 2H), 7.53-7.46 (m, 2H), 7.45-7.40 (m,2H), 7.37-7.31 (m, 3H), 7.31-7.26 (m, 1H), 7.24-7.18 (m, 2H), 5.09 (d,1H), 4.72 (td, 1H), 3.71 (dd, 1H), 3.58 (td, 1H), 3.44 (dd, 1H), 1.56(tt, 1H), 1.09-1.02 (m, 2H), 0.85-0.78 (m, 2H).

EXAMPLE 151N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide

Step-1:

To a stirred solution of 1-(5-chlorothiophen-2-yl)ethan-1-one (20 g, 125mmol, 1.0 eq) in EtOH (250 mL) at RT were added NaOAc (50.6 g, 625 mmol,5.0 eq) and NH₂OH.HCl (25.7 g, 375 mmol, 3.0 eq) and stirred for 16 h at80° C. The reaction progress was monitored by TLC. The reaction mixturewas evaporated, diluted with H₂O and the formed precipitate was washedwith H₂O (100 mL) and dried under vacuum to get(E)-1-(5-chlorothiophen-2-yl)ethan-1-one oxime (20 g, 94%) as a brownliquid.

Step-2:

To a stirred solution of compound(E)-1-(5-chlorothiophen-2-yl)ethan-1-one oxime (10 g, 57.14 mmol, 1.0eq) in DCM (100 mL) at −40° C. were added TEA (9.2 mL, 68.57 mmol, 1.2eq) and the mixture was stirred for 15 min prior to the addition ofchlorodiphenylphosphine (13.8 g, 62.85 mmol, 1.1 eq). The reaction wasslowly allowed to warm up to rt and stirred for 2 h. The reactionprogress was monitored by TLC. The reaction mixture was diluted with H₂O(100 mL), and extracted with DCM (2×200 mL). The combined organic layerwas washed with brine (100 mL), dried over Na₂SO₄ and evaporated. Thecrude product was purified by flash chromatography (silica 40-60% EtOAcin petroleum ether as an eluent) to get compound(E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphinic amide(15 g, 73%) as a brown solid.

Step-3:

To a stirred solution of compound(E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphinic amide(15 g, 41.71 mmol, 1.0 eq) in THF (200 mL) at RT were under nitrogenatmosphere added Cu(OAc)₂ (0.377 g, 2.85 mmol, 0.05 eq), TPP (1.0 g,4.16 mmol, 0.1 eq). The mixture was stirred for 15 min prior to theaddition of diethyl fumarate (18 mL, 104 mmol, 2.5 eq), andpinacolborane (14.8 mL, 116 mmol, 2.8 eq). Stirring was continued for 16h at RT. The reaction progress was monitored by TLC. The reactionmixture was diluted with water (100 mL) and extracted with EtOAc (2×100mL). The combined organic layers were washed with brine (100 mL), dried(Na₂SO₄) and evaporated. The crude compound was purified by flashchromatography (silica 40-60% EtOAc in petroleum ether as an eluent) toget compound ethyl2-(5-chlorothiophen-2-yl)-1-(diphenylphosphoryl)-2-methyl-5-oxopyrrolidine-3-carboxylate(15 g, −75%) as a white solid.

Step-4:

To a stirred solution of compound ethyl2-(5-chlorothiophen-2-yl)-1-(diphenylphosphoryl)-2-methyl-5-oxopyrrolidine-3-carboxylate(15 g, 30.80 mmol, 1.0 eq) in EtOH (150 mL) at RT was added conc. HCl(15 mL) and stirred for 16 h at 90° C. The reaction progress wasmonitored by TLC. The reaction mixture was evaporated, diluted withwater (50 mL), basified with sat NaHCO₃ (pH=8), and extracted with EtOAc(2×200 mL). The combined organic layers were washed with brine (100 mL),dried (Na₂SO₄) and evaporated. The crude compound was purified by flashchromatography (silica 60-70% EtOAc in petroleum ether as an eluent) toget compound ethylrac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxylate(7.0 g, −81%) as white solid.

Step-5:

To a stirred solution of compound ethyl(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxylate(7 g, 24.39 mmol, 1.0 eq) in THF/MeOH/H₂O (1:1:1, 75 mL) at RT was addedLiOH*H₂O (1.7 g, 48.78 mmol, 2.0 eq) at Rt and stirring was continued atthe same temperature. The reaction progress was monitored by TLC. Thereaction mixture was evaporated, diluted with water (30 mL), andextracted with Et₂O (2×50 mL). The aqueous layer was acidified with 1NHCl (pH=4-5), and precipitate formed was filtered and dried to getcompound(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxylicacid (3.5 g, −97%) as white solid.

Step-6:

To a stirred solution of compoundrac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3-carboxylicacid (3.4 g, 13.12 mmol, 1.0 eq) in toluene (70 mL) at RT were added TEA(2.0 mL, 13.78 mmol, 1.05 eq), DPPA (3.4 mL, 15.74 mmol, 1.2 eq).Stirring was continued for 2 h at 90° C., the mixture was then cooled toRT, prior to the addition of BnOH (3 mL, 26.25 mmol, 2.0 eq). Theresulting mixture was heated for 16 h to 120° C. The reaction progresswas monitored by TLC. The reaction mixture was evaporated, diluted withwater (50 mL) and extracted with EtOAc (2×100 mL). The combined organiclayers were washed with brine (50 mL), dried (Na₂SO₄) and evaporated.The crude compound was purified by flash chromatography (silica 70-90%EtOAc in petroleum ether as an eluent) to get compound benzyl(rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)carbamate(2.0 g, −41%) as an off-white solid.

Step-7:

A stirred solution of compound benzyl(rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)carbamate(2.0 g, 5.49 mmol, 1.0 eq) in HBr in AcOH (20 mL) at RT was stirred for2 h at RT. The reaction progress was monitored by TLC. The reactionmixture was quenched with NaHCO₃ solution and extracted with EtOAc(4×100 mL). The combined organic layers were washed with brine (50 mL),dried (Na₂SO₄) and evaporated. The crude compound was purified by byflash chromatography (silica 70-80% EtOAc in petroleum ether as aneluent) to get compoundrac-(4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-5-methylpyrrolidin-2-one(1.0 g, −41%) as an off-white solid.

Step-8:

To a stirred solution of compoundrac-(4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-5-methylpyrrolidin-2-one(400 mg, 1.739 mmol, 1.0 eq) and cyclopropane carboxylic acid (224 mg,2.608 mmol, 1.5 eq) in DMF (10 mL) at 0° C. under nitrogen atmospherewere added HATU (0.90 g, 2.608 mmol, 1.5 eq), DIPEA (0.9 mL, 5.217 mmol,3.0 eq) and stirred for 16 h at RT. The reaction progress was monitoredby TLC. The reaction mixture was diluted with water (20 mL) andextracted with EtOAc (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄) and evaporated. The crude compoundwas purified by by flash chromatography (silica 70-90% EtOAc inpetroleum ether as an eluent) to get compoundN-(rac(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(210 mg, −40%).

Step-9:

To a stirred solution of compoundN-(rac(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(200 mg, 0.671 mmol, 1.0 eq) and compound1-(4-fluorophenyl)-5-iodo-1H-indazole (249 mg, 0.738 mmol, 1.5 eq) indioxane (10 mL) under nitrogen atmosphere were added CuI (127 mg, 0.671mmol, 1.5 eq), DMEDA (59 mg 0.671 mmol, 1 eq), and K₂CO₃ (277 mg, 2.013mmol, 3.0 eq) and stirred at 130° C. for 16 h. The reaction progress wasmonitored by TLC. The reaction mixture was diluted with water (20 mL)and extracted with EtOAc (2×20 mL). The combined organic layers werewashed with brine (20 mL), dried (Na₂SO₄) and evaporated. The crudecompound was purified by by flash chromatography (silica 70-90% EtOAc inpetroleum ether as an eluent) followed by prep HPLC to get Example 151N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(50 mg, −53%).

¹HNMR (500 MHz, DMSO-d₆): δ 8.77 (d, 1H), 8.39 (s, 1H), 7.80-7.76 (m,3H), 7.58 (d, 1H), 7.63 (s, 1H), 7.44-7.40 (m, 2H), 7.22 (dd, 1H), 7.01(d, 1H), 6.93 (d, 1H), 4.71-4.67 (m, 1H), 3.10 (dd, 1H), 2.43-2.36 (m,1H), 1.64-1.61 (m, 1H), 1.48 (s, 3H), 0.72-0.6 (m, 4H).

The examples in the following table were synthesized in analogy toExample 1 described above, using different intermediates.

Inter- Ex. mediate Yield # (INT) Structure (%) ¹H NMR 4 Int A3

12 ¹H NMR (DMSO-d₆): δ = 9.08 (d, 1H), 8.31 (s, 1H), 7.72-7.69 (m, 4H),7.41-7.34 (m, 5H), 7.24(s, 2H), 7.17(m, 1H), 5.41 (d, 1H), 4.26 (t, 1H),1.71 (t, 3H), 1.27 (s, 3H), 1.13 (s, 3H). 9 Int A3

10 ¹H NMR (DMSO-d₆): δ = 9.07 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H),7.68-7.58 (m, 3H), 7.34-7.17 (m, 6H), 6.51 (s, 1H), 5.39 (s, 1H), 4.25(s, 1H), 3.48 (s, 3H), 1.71 (t, 3H), 1.27 (s, 3H), 1.13 (s, 3H) 10 IntA3

13 ¹H NMR (DMSO-d₆): δ = 9.08 (d, 1H), 8.31 (s, 1H), 7.72-7.69 (m, 4H),7.41-7.34 (m, 5H), 7.24(s, 2H), 7.17(m, 1H), 5.41 (d, 1H), 4.26 (t, 1H),1.71 (t, 3H), 1.27 (s, 3H), 1.13 (s, 3H).

The examples in the following table were synthesized in analogy toExample 5 described above, using different intermediates.

Inter- Ex. mediate Yield # (INT) Structure (%) ¹H NMR 3 Int A5

10 ¹H NMR (DMSO-d₆) δ: 8.90 (d, 1H), 8.30 (t, 1H), 7.93 (dd, 1H),7.79-7.69 (m, 4H), 7.43-7.37 (m, 4H), 7.34 (t, 2H), 7.28-7.21 (m, 1H),5.29 (d, 1H), 4.03 (dd, 1H), 1.68 (tt, 1H), 1.31-0.91 (m, 4H), 0.80-0.62(m, 4H) 30 Int A5

4 ¹H NMR (DMSO-d₆) δ: 8.89 (d, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.92(dd, 1H), 7.71 (ddd, 2H), 7.61 (dt, 1H), 7.41-7.36 (m, 2H), 7.33 (t,2H), 7.27-7.21 (m, 1H), 6.54 (dd, 1H), 5.28 (d, 1H), 4.03 (dd, 1H), 3.50(s, 3H), 1.72-1.64 (m, 1H), 1.26-1.15 (m, 1H), 1.16-1.08 (m, 1H), 0.95(q, 2H), 0.74 (ddd, 1H), 0.73-0.68 (m, 3H)

The examples in the following table were synthesized in analogy toExample 7 described above, using different intermediates.

Inter- Ex. mediate Yield # (INT) Structure (%) ¹H NMR  6 Int A 4 ent 1

31 ¹H NMR (DMSO-d₆) δ: 9.11 (d, 1H), 8.26 (d, 1H), 8.17 (d, 1H), 7.78(t, 1H), 7.72-7.67 (m, 2H), 7.59 (d, 1H), 7.40 (d, 1H), 7.39- 7.35 (m,2H), 7.22 (t, 2H), 7.17- 7.11 (m, 1H), 6.54 (d, 1H), 5.63 (d, 1H), 4.46(t, 1H), 3.50 (s, 3H), 2.52 (s, 3H), 1.32 (s, 3H), 1.18 (s, 3H)  12 IntA 4 ent 1

80 ¹H NMR (DMSO-d₆) δ: 8.39 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H), 7.78(d, 1H), 7.72-7.68 (m, 2H), 7.59 (d, 1H), 7.40 (dd, 1H), 7.38- 7.35 (m,2H), 7.21 (t, 2H), 7.15- 7.10 (m, 1H), 6.57 (d, 1H), 6.54 (d, 1H), 5.59(d, 1H), 4.50 (t, 1H), 3.96 (s, 3H), 3.50 (s, 3H), 1.30 (s, 3H), 1.17(s, 3H)  13 Int A 4 ent 1

85 ¹H NMR (DMSO-d₆) δ: 8.96 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.18(d, 1H), 7.83 (s, 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.62-7.57 (m, 1H),7.41 (dd, 1H), 7.39- 7.36 (m, 2H), 7.23 (t, 2H), 7.18- 7.12 (m, 1H),6.54 (d, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 3.50 (s, 3H), 1.31 (s, 3H),1.18 (s, 3H)  14 Int A 4 ent 1

64 ¹H NMR (DMSO-d₆) δ: 9.38 (d, 1H), 8.26 (d, 1H), 8.18 (d, 1H),7.72-7.67 (m, 2H), 7.62-7.57 (m, 1H), 7.41-7.37 (m, 3H), 7.24 (t, 2H),7.18-7.13 (m, 1H), 6.54 (d, 1H), 5.55 (d, 1H), 4.50 (t, 1H), 3.50 (s,3H), 2.69 (s, 3H), 1.33 (s, 3H), 1.18 (s, 3H)  15 Int A 4 ent 1

70 ¹H NMR (DMSO-d₆) δ: 9.25 (d, 1H), 8.95 (dd, 1H), 8.60 (s, 1H), 8.26(d, 1H), 8.18 (d, 1H), 7.75 (dd, 1H), 7.74-7.67 (m, 1H), 7.60 (dd, 1H),7.46-7.41 (m, 1H), 7.39 (dd, 2H), 7.24 (t, 2H), 7.18-7.12 (m, 1H), 6.54(d, 1H), 5.36 (d, 1H), 4.51-4.45 (m, 1H), 3.50 (d, 3H), 1.32 (s, 3H),1.20 (s, 3H)  16 Int A 4 ent 1

60 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.61 (dd, 1H), 8.25 (d, 1H), 8.18(d, 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.59 (d, 1H), 7.42 (dd, 1H),7.40-7.37 (m, 2H), 7.25 (t, 2H), 7.20-7.14 (m, 1H), 6.54 (d, 1H), 5.37(d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18(s, 3H)  17 Int A 4 ent 1

87 ¹H NMR (DMSO-d₆) δ: 9.25 (d, 1H), 8.79 (d, 1H), 8.30 (d, 1H), 8.26(d, 1H), 8.17 (d, 1H), 7.72- 7.68 (m, 2H), 7.61-7.57 (m, 1H), 7.41 (dd,1H), 7.39-7.36 (m, 2H), 7.21 (t, 2H), 7.15-7.10 (m, 1H), 6.54 (d, 1H),5.64 (d, 1H), 4.53 (t, 1H), 3.50 (s, 3H), 1.33 (s, 3H), 1.19 (s, 3H)  18Int A 4 ent 1

73 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.61 (dd, 1H), 8.25 (d, 1H), 8.18(d, 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.61-7.57 (m, 1H), 7.42 (dd, 1H),7.40-7.36 (m, 2H), 7.25 (t, 2H), 7.20-7.14 (m, 1H), 6.54 (d, 1H), 5.37(d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18(s, 3H)  21 Int A 4 ent 2

77 ¹H NMR (DMSO-d₆) δ: 8.95 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.17(d, 1H), 7.83 (s, 1H), 7.74- 7.72 (m, 1H), 7.70 (dd, 1H), 7.62- 7.57 (m,1H), 7.41 (dd, 1H), 7.39-7.36 (m, 2H), 7.23 (t, 2H), 7.17-7.12 (m, 1H),6.54 (d, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 3.50 (s, 3H), 1.31 (s, 3H),1.18 (s, 3H)  22 Int A 4 ent 2

80 ¹H NMR (DMSO-d₆) δ: 9.08 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H),7.72-7.67 (m, 2H), 7.59 (d, 1H), 7.42-7.35 (m, 3H), 7.23 (t, 2H),7.18-7.12 (m, 1H), 6.53 (d, 1H), 6.50 (t, 1H), 5.50 (d, 1H), 4.47 (t,1H), 3.50 (s, 3H), 2.47 (d, 3H), 1.32 (s, 3H), 1.17 (s, 3H)  24 Int A 4ent 2

78 ¹H NMR (DMSO-d₆) δ: 9.25 (d, 1H), 8.95 (dd, 1H), 8.60 (s, 1H), 8.26(d, 1H), 8.18 (d, 1H), 7.76- 7.73 (m, 1H), 7.70 (dd, 1H), 7.62- 7.57 (m,1H), 7.43 (dd, 1H), 7.41-7.37 (m, 2H), 7.24 (t, 2H), 7.18-7.12 (m, 1H),6.54 (d, 1H), 5.36 (d, 1H), 4.48 (t, 1H), 3.50 (s, 3H), 1.32 (s, 3H),1.20 (s, 3H)  26 Int A 4 ent 2

63 ¹H NMR (DMSO-d₆) δ: 9.10 (d, 1H), 8.26 (d, 1H), 8.17 (d, 1H),7.80-7.75 (m, 1H), 7.72-7.67 (m, 2H), 7.61-7.56 (m, 1H), 7.41- 7.35 (m,3H), 7.22 (t, 2H), 7.17- 7.11 (m, 1H), 6.53 (d, 1H), 5.62 (d, 1H), 4.45(t, 1H), 3.50 (s, 3H), 2.53-2.51 (m, 3H), 1.32 (s, 3H), 1.18 (s, 3H) 36a Int A 7 ent 1

86 ¹H NMR (DMSO-d₆) δ: 8.97 (d, 1H), 8.60 (s, 1H), 8.31 (d, 1H), 7.83(s, 1H), 7.76-7.72 (m, 3H). 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.35 (m,4H), 7.23 (dd, 2H), 7.17-7.12 (m, 1H), 5.42 (d, 1H), 4.49 (t, 1H), 1.31(s, 3H), 1.18 (d, 3H)  36b Int A 7 ent 2

40 ¹H NMR (DMSO-d₆) δ: 8.97 (d, 1H), 8.60 (s, 1H), 8.31 (d, 1H), 7.83(s, 1H), 7.76-7.72 (m, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.35 (m,4H), 7.23 (dd, 2H), 7.17-7.12 (m, 1H), 5.42 (d, 1H), 4.49 (t, 1H), 1.31(s, 3H), 1.18 (d, 3H)  37 Int A7 ent 1

71 ¹H NMR (DMSO-d₆) δ: 8.40 (d, 1H), 8.31 (d, 1H), 7.78 (d, 1H),7.76-7.71 (m, 3H), 7.69 (dd, 1H), 7.44 (dd, 1H), 7.41-7.35 (m, 4H),7.24-7.18 (m, 2H), 7.16- 7.10 (m, 1H), 6.58 (dd, 1H), 5.59 (dd, 1H),4.51 (t, 1H), 3.96 (d, 3H), 1.31 (d, 3H), 1.17 (s, 3H)  38a Int A7 ent 2

44 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.67-8.57 (m, 1H), 8.31 (d, 1H),7.80-7.64 (m, 4H), 7.46 (dd, 1H), 7.42-7.35 (m, 4H), 7.25 (dd, 2H),7.19-7.13 (m, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.51 (s, 3H), 1.34 (s,3H), 1.18 (s, 3H)  38b Int A7 ent 1

92 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.67-8.57 (m, 1H), 8.31 (d, 1H),7.80-7.64 (m, 4H), 7.46 (dd, 1H), 7.42-7.35 (m, 4H), 7.25 (dd, 2H),7.19-7.13 (m, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.51 (s, 3H), 1.34 (s,3H), 1.18 (s, 3H)  39a Int A7 ent 1

88 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.63-8.58 (m, 1H), 8.31 (d, 1H),7.78-7.72 (m, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m, 4H),7.25 (t, 2H), 7.17 (t, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.52 (s, 3H),1.34 (s, 3H), 1.18 (s, 3H)  39b Int A7 ent 2

51 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.63-8.58 (m, 1H), 8.31 (d, 1H),7.78-7.72 (m, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m, 4H),7.25 (t, 2H), 7.17 (t, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.52 (s, 3H),1.34 (s, 3H), 1.18 (s, 3H)  40a Int A7 ent 1

98 ¹H NMR (DMSO-d₆) δ: 9.37 (d, 1H), 8.64 (d, 1H), 8.31 (d, 1H), 7.78(dd, 1H), 7.77-7.71 (m, 2H), 7.70 (dd, 1H), 7.47 (dd, 1H), 7.43-7.35 (m,4H), 7.24 (dd, 2H), 7.19-7.13 (m, 1H), 5.25 (d, 1H), 4.46 (t, 1H), 2.30(s, 3H), 1.31 (s, 3H), 1.18 (s, 3H)  40b Int A7 ent 2

62 ¹H NMR (DMSO-d₆) δ: 9.37 (d, 1H), 8.64 (d, 1H), 8.31 (d, 1H), 7.78(dd, 1H), 7.77-7.71 (m, 2H), 7.70 (dd, 1H), 7.47 (dd, 1H), 7.43-7.35 (m,4H), 7.24 (dd, 2H), 7.19-7.13 (m, 1H), 5.25 (d, 1H), 4.46 (t, 1H), 2.30(s, 3H), 1.31 (s, 3H), 1.18 (s, 3H)  41a Int A7 ent 1

79 ¹H NMR (DMSO-d₆) δ: 8.31 (d, 1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.88(d, 1H), 7.78-7.71 (m, 3H), 7.73-7.68 (m, 1H), 7.46 (dd, 1H), 7.43-7.33(m, 4H), 7.22 (dd, 2H), 7.17-7.11 (m, 1H), 5.30 (d, 1H), 4.47 (t, 1H),3.87 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H)  41b Int A7 ent 2

35 ¹H NMR (DMSO-d₆) δ: 8.31 (d, 1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.88(d, 1H), 7.78-7.71 (m, 3H), 7.73-7.68 (m, 1H), 7.46 (dd, 1H), 7.43-7.33(m, 4H), 7.22 (dd, 2H), 7.17-7.11 (m, 1H), 5.30 (d, 1H), 4.47 (t, 1H),3.87 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H)  42a Int A7 ent 1

89 ¹H NMR (DMSO-d₆) δ: 9.02 (d, 1H), 8.96-8.91 (m, 1H), 8.77- 8.72 (m,1H), 8.32 (d, 1H), 8.21- 8.16 (m, 1H), 7.78 (d, 1H), 7.76- 7.73 (m, 2H),7.71 (d, 1H), 7.55 (dd, 1H), 7.48 (dd, 1H), 7.43- 7.36 (m, 4H),7.27-7.21 (m, 2H), 7.18-7.12 (m, 1H), 5.41 (d, 1H), 4.55 (t, 1H), 1.34(s, 3H), 1.21 (s, 3H)  42b Int A7 ent 2

27 ¹H NMR (DMSO-d₆) δ: 9.02 (d, 1H), 8.96-8.91 (m, 1H), 8.77- 8.72 (m,1H), 8.32 (d, 1H), 8.21- 8.16 (m, 1H), 7.78 (d, 1H), 7.76- 7.73 (m, 2H),7.71 (d, 1H), 7.55 (dd, 1H), 7.48 (dd, 1H), 7.43- 7.36 (m, 4H),7.27-7.21 (m, 2H), 7.18-7.12 (m, 1H), 5.41 (d, 1H), 4.55 (t, 1H), 1.34(s, 3H), 1.21 (s, 3H)  43a Int A7 ent 1

96 ¹H NMR (DMSO-d₆) δ: 9.23 (d, 1H), 9.00 (d, 2H), 8.31 (d, 1H), 7.76(dd, 1H), 7.73 (ddd, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m,4H), 7.22 (t, 2H), 7.16- 7.11 (m, 1H), 5.64 (d, 1H), 4.56 (dd, 1H), 1.35(s, 3H), 1.22 (s, 3H)  43b Int A7 ent 2

35 ¹H NMR (DMSO-d₆) δ: 9.23 (d, 1H), 9.00 (d, 2H), 8.31 (d, 1H), 7.76(dd, 1H), 7.73 (ddd, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43- 7.36 (m,4H), 7.22 (t, 2H), 7.16- 7.11 (m, 1H), 5.64 (d, 1H), 4.56 (dd, 1H), 1.35(s, 3H), 1.22 (s, 3H)  44a Int A7 ent 1

90 ¹H NMR (DMSO-d₆) δ: 8.81 (dd, 1H), 8.31 (s, 1H), 7.77-7.65 (m, 5H),7.45 (dd, 1H), 7.43-7.35 (m, 4H), 7.23 (t, 2H), 7.18-7.12 (m, 1H), 5.41(d, 1H), 4.48 (t, 1H), 2.51 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H)  44b IntA7 ent 2

37 ¹H NMR (DMSO-d₆) δ: 8.81 (dd, 1H), 8.31 (s, 1H), 7.77-7.65 (m, 5H),7.45 (dd, 1H), 7.43-7.35 (m, 4H), 7.23 (t, 2H), 7.18-7.12 (m, 1H), 5.41(d, 1H), 4.48 (t, 1H), 2.51 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H)  45a IntA7 ent 1

89 ¹H NMR (DMSO-d₆) δ: 8.77 (d, 1H), 8.50 (s, 1H), 8.31 (t, 1H),7.77-7.72 (m, 3H), 7.70 (dd, 1H), 7.44 (dd, 1H), 7.42-7.35 (m, 4H), 7.23(t, 2H), 7.18-7.12 (m, 1H), 5.51 (d, 1H), 4.49 (t, 1H), 2.32 (s, 3H),1.32 (s, 3H), 1.17 (s, 3H)  45b Int A7 ent 2

62 ¹H NMR (DMSO-d₆) δ: 8.77 (d, 1H), 8.50 (s, 1H), 8.31 (t, 1H),7.77-7.72 (m, 3H), 7.70 (dd, 1H), 7.44 (dd, 1H), 7.42-7.35 (m, 4H), 7.23(t, 2H), 7.18-7.12 (m, 1H), 5.51 (d, 1H), 4.49 (t, 1H), 2.32 (s, 3H),1.32 (s, 3H), 1.17 (s, 3H)  46 A9

26 ¹H NMR (DMSO-d₆) δ: 8.57 (d, 1H), 8.29 (t, 1H), 7.78 (d, 1H),7.77-7.71 (m, 2H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.39 (td, 2H), 7.33 (d,2H), 7.24 (t, 2H), 7.19-7.11 (m, 1H), 5.19 (d, 1H), 4.04 (td, 1H),2.78-2.70 (m, 1H), 1.57 (tt, 1H), 1.24 (d, 3H), 0.74-0.58 (m, 4H).  47A13- trans

43 ¹H NMR (DMSO-d₆) δ: 9.21 (s, 1H), 8.33 (s, 1H), 7.73 (dt, 4H),7.53-7.46 (m, 1H), 7.45-7.32 (m, 3H), 7.27-7.15 (m, 2H), 5.85 (s, 1H),4.16 (s, 1H), 2.96 (dd, 1H), 2.55 (d, 0H), 1.73 (t, 3H), 1.28 (d, 3H) 60 A9

30 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.70 (d, 1H), 8.29 (d, 1H), 7.80(dd, 1H), 7.76-7.72 (m, 2H), 7.68 (dt, 1H), 7.51 (dd, 1H), 7.43-7.34 (m,4H), 7.28-7.22 (m, 2H), 7.20-7.14 (m, 1H), 5.33 (d, 1H), 4.27 (td, 1H),2.89 (dq, 1H), 2.56 (s, 3H), 1.31 (d, 3H)  63 A11- trans

55 ¹H NMR (DMSO-d₆) δ: 8.56 (d, 1H), 8.30 (d, 1H), 7.79 (dd, 1H),7.77-7.71 (m, 2H), 7.69 (dd, 1H), 7.56-7.48 (m, 1H), 7.43- 7.36 (m, 2H),7.17-7.07 (m, 3H), 6.97 (ddt, 1H), 5.15 (d, 1H), 4.01 (td, 1H),2.76-2.68 (m, 1H), 2.20 (s, 3H), 1.57 (tt, 1H), 1.23 (d, 3H), 0.74 0.58(m, 4H)  64 A9

28 ¹H NMR (DMSO-d₆) δ: 8.60 (d, 1H), 8.29 (d, 1H), 7.78 (d, 1H),7.77-7.70 (m, 3H), 7.68 (dt, 1H), 7.46 (dd, 1H), 7.43-7.36 (m, 2H),7.34-7.29 (m, 2H), 7.21 (dd, 2H), 7.16-7.10 (m, 1H), 6.56 (d, 1H), 5.37(d, 1H), 4.34 (td, 1H), 3.94 (s, 3H), 2.92 (dq, 1H), 1.26 (d, 3H)  65 A9

44 ¹H NMR (DMSO-d₆) δ: 9.11 (d, 1H), 9.07 - 8.99 (m, 1H), 8.74 (dd, 1H),8.30 (d, 1H), 8.23 8.18 (m, 1H), 7.82 (dd, 1H), 7.78- 7.71 (m, 2H), 7.70(dt, 1H), 7.57- 7.51 (m, 2H), 7.43-7.36 (m, 4H), 7.24 (dd, 2H),7.19-7.13 (m, 1H), 5.38 (d, 1H), 4.32 (td, 1H), 2.92 (dq, 1H), 1.32 (d,3H)  66 A9

35 ¹H NMR (DMSO-d₆) δ: 9.45 (d, 1H), 9.00 (d, 2H), 8.30 (d, 1H),7.78-7.69 (m, 4H), 7.68 (dd, 1H), 7.48 (dd, 1H), 7.44-7.36 (m, 2H),7.36-7.32 (m, 2H), 7.24- 7.19 (m, 2H), 7.17-7.11 (m, 1H), 5.44 (d, 1H),4.40 (td, 1H), 3.02-2.94 (m, 1H), 1.30 (d, 3H)  67 A11- trans

43 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.70 (d, 1H), 8.30 (d, 1H), 7.80(d, 1H), 7.77-7.71 (m, 2H), 7.69 (d, 1H), 7.51 (dd, 1H), 7.45- 7.36 (m,2H), 7.18 (d, 1H), 7.17- 7.10 (m, 2H), 6.98 (dt, 1H), 5.28 (d, 1H), 4.23(td, 1H), 2.94-2.78 (m, 1H), 2.57 (s, 3H), 2.20 (s, 3H), 1.31 (d, 3H) 68 A11- trans

54 ¹H NMR (DMSO-d₆) δ: 9.10 (d, 1H), 9.04 (d, 1H), 8.74 (dd, 1H), 8.31(d, 1H), 8.20 (dt, 1H), 7.82 (d, 1H), 7.78-7.72 (m, 2H), 7.71 (dd, 1H),7.57-7.51 (m, 2H), 7.43-7.36 (m, 2H), 7.21 (t, 1H), 7.19-7.10 (m, 2H),6.97 (d, 1H), 5.33 (d, 1H), 4.30 (td, 1H), 2.90 (dq, 1H), 2.19 (s, 3H),1.32 (d, 3H)  69 A11- trans

23 ¹H NMR (DMSO-d₆) δ: 9.47 9.42 (m, 1H), 9.00 (d, 1H), 8.31 (s, 1H),7.78-7.73 (m, 2H), 7.76- 7.69 (m, 2H), 7.69 (d, 1H), 7.48 (dd, 1H),7.43-7.36 (m, 2H), 7.18-7.07 (m, 4H), 6.95 (d, 1H), 5.39 (d, 1H), 4.39(td, 1H), 2.97 (dq, 1H), 2.17 (s, 3H), 1.30 (d, 3H)  70 A11-cis

52 ¹H NMR (DMSO-d₆) δ: 8.76 (d, 1H), 8.32 (s, 1H), 7.96 (d, 1H), 7.80(ddd, 1H), 7.79-7.71 (m, 3H), 7.44-7.37 (m, 2H), 7.22 (t, 1H), 7.18 (d,1H), 7.14-7.09 (m, 1H), 7.07 (d, 1H), 5.15 (d, 1H), 4.35 (ddd, 1H), 3.04(p, 1H), 2.27 (s, 3H), 1.78-1.68 (m, 1H), 1.11 (d, 3H), 0.80-0.73 (m,1H), 0.76- 0.70 (m, 2H)  71 A11-cis

49 ¹H NMR (DMSO-d₆) δ: 9.08 (s, 0H), 9.01 (d, 1H), 8.32 (d, 1H), 7.94(dd, 1H), 7.79-7.71 (m, 4H), 7.44-7.36 (m, 2H), 7.26- 7.21 (m, 2H),7.20-7.15 (m, 1H), 7.08 (ddt, 1H), 5.32 (d, 1H), 4.52 (td, 1H), 3.16 (p,1H), 2.60 (s, 3H), 2.28 (d, 3H), 2.08 (s, 1H), 1.16 (d, 3H)  72 A11-cis

48 1H NMR (DMSO-d6) δ: 8.79 (d, 1H), 8.32 (s, 1H), 7.91 (dd, 1H),7.81-7.67 (m, 6H), 7.44-7.36 (m, 2H), 7.23-7.13 (m, 3H), 7.07- 7.02 (m,1H), 6.66 (d, 1H), 5.40 (d, 1H), 4.57 (td, 1H), 3.93 (s, 3H), 3.12 (p,1H), 2.25 (s, 3H), 1.11 (d, 3H)  73 A11-cis

45 1H NMR (DMSO-d6) δ: 9.28 (d, 1H), 9.09 (d, 1H), 8.74 (dd, 1H), 8.32(t, 1H), 8.27 (dt, 1H), 7.98 (d, 1H), 7.80 (dd, 1H), 7.78-7.71 (m, 3H),7.54 (ddd, 1H), 7.44- 7.37 (m, 2H), 7.27-7.21 (m, 2H), 7.21-7.16 (m,1H), 7.08 (d, 1H), 5.37 (d, 1H), 4.62 (ddd, 1H), 3.19 (p, 1H), 2.28 (s,3H), 1.17 (d, 3H)  74 A11-cis

49 1H NMR (DMSO-d6) δ: 9.53 (d, 1H), 9.00 (dd, 1H), 9.90-6.59 (m, 0H),8.32 (d, 1H), 7.93 (dd, 1H), 7.79-7.69 (m, 6H), 7.44- 7.36 (m, 2H),7.25-7.16 (m, 3H), 7.06 (dd, 1H), 5.45 (d, 1H), 4.62 (td, 1H), 3.24-3.16(m, 1H), 2.26 (s, 3H), 1.15 (d, 3H)  75 A11- trans

86 ¹H NMR (DMSO-d₆) δ: 8.59 (d, 1H), 8.30 (d, 1H), 7.78 (d, 1H),7.78-7.71 (m, 3H), 7.69 (dt, 1H), 7.46 (dd, 1H), 7.43-7.31 (m, 2H),7.16-7.07 (m, 3H), 6.97- 6.92 (m, 1H), 6.57 (d, 1H), 5.33 (d, 1H), 4.32(td, 1H), 3.94 (s, 3H), 2.90 (dq, 1H), 2.17 (s, 3H), 1.26 (d, 3H)  77A11-cis

54 ¹H NMR (DMSO-d₆) δ: 9.45 (d, 1H), 8.33 (d, 1H), 7.92 (t, 1H),7.81-7.69 (m, 4H), 7.47-7.35 (m, 2H), 7.29 7.16 (m, 2H), 7.16- 7.10 (m,1H), 7.10-7.03 (m, 1H), 5.28 (d, 1H), 4.41 (td, 1H), 3.16 (p, 1H), 2.26(s, 3H), 1.81 (t, 3H), 1.08 (d, 3H)  78 A13-cis

41 1H NMR (DMSO-d6) δ: 8.82 (d, 1H), 8.36 (d, 1H), 7.97 (d, 1H),7.82-7.73 (m, 4H), 7.51 (dd, 1H), 7.44-7.38 (m, 2H), 7.38- 7.26 (m, 4H),5.50 (d, 1H), 4.49 (ddd, 1H), 3.03 (p, 1H), 1.68 (tt, 1H), 1.05 (d, 3H),0.77-0.67 (m, 4H)  79 A13-cis

54 ¹H NMR (DMSO-d₆) δ: 9.58 (d, 1H), 8.36 (d, 1H), 7.95 (dd, 1H),7.83-7.69 (m, 4H), 7.52 (dt, 1H), 7.46-7.35 (m, 2H), 7.38-7.25 (m, 3H),5.62 (d, 1H), 4.48 (t, 1H), 3.22 3.11 (m, 1H), 1.82 (t, 3H), 1.11-1.01(m, 4H)  80 A9

33 ¹H NMR (DMSO-d₆) δ: 9.17 (d, 1H), 8.29 (s, 1H), 7.79-7.70 (m, 3H),7.68 (d, 1H), 7.47 (dd, 1H), 7.44-7.35 (m, 2H), 7.35-7.29 (m, 2H), 7.24(t, 2H), 7.20-7.12 (m, 1H), 5.27 (d, 1H), 4.12 (q, 1H), 2.87 (dq, 1H),1.73 (t, 3H), 1.26 (d, 3H)  81 A11- trans

62 ¹H NMR (DMSO-d₆) δ: 9.16 (d, 1H), 8.30 (d, 1H), 7.78-7.72 (m, 3H),7.69 (d, 1H), 7.48 (dd, 1H), 7.44-7.35 (m, 2H), 7.15-7.08 (m, 3H), 6.98(dt, 1H), 5.22 (d, 1H), 4.14-4.04 (m, 1H), 2.85 (dq, 1H), 2.20 (s, 3H),1.73 (t, 3H), 1.26 (d, 3H)  82 A15- trans

23 ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.65 (d, 1H), 8.30 (s, 1H),7.79-7.71 (m, 3H), 7.68 (d, 1H), 7.48 (dd, 1H), 7.40 (t, 2H), 7.29 (d,2H), 6.79 (d, 2H), 5.25 (d, 1H), 4.26 (td, 1H), 3.64 (s, 3H), 2.87 (dq,1H), 2.57 (s, 3H), 1.31 (d, 3H)  83 A15- trans

18 ¹H NMR (DMSO-d₆) δ: 8.54 (d, 1H), 8.29 (d, 1H), 7.79-7.73 (m, 2H),7.75-7.70 (m, 2H), 7.67 (dt, 1H), 7.43 (dd, 1H), 7.43 7.36 (m, 2H),7.27-7.21 (m, 2H), 6.79- 6.73 (m, 2H), 6.56 (d, 1H), 5.30 (d, 1H), 4.33(td, 1H), 3.94 (s, 3H), 3.63 (s, 3H), 2.90 (dq, 1H), 1.26 (d, 3H)  84A15- trans

30 ¹H NMR (DMSO-d₆) δ: 9.08- 9.02 (m, 2H), 8.74 (dd, 1H), 8.31 (d, 1H),8.20 (ddd, 1H), 7.79 (dd, 1H), 7.78-7.72 (m, 2H), 7.69 (dt, 1H), 7.54(ddd, 1H), 7.50 (dd, 1H), 7.43-7.36 (m, 2H), 7.33- 7.28 (m, 2H),6.81-6.76 (m, 2H), 5.30 (d, 1H), 4.32 (tdd, 1H), 3.64 (s, 3H), 2.89 (dq,1H), 1.32 (d, 3H)  85 A15- trans

30 ¹H NMR (DMSO-d₆) δ: 9.39 (d, 1H), 8.99 (dd, 2H), 8.30 (d, 1H),7.76-7.73 (m, 3H), 7.71 (td, 1H), 7.68 (dd, 1H), 7.44 (dd, 1H), 7.43-7.36 (m, 2H), 7.29-7.24 (m, 2H), 6.79-6.73 (m, 2H), 5.36 (d, 1H), 4.40(td, 1H), 3.63 (d, 3H), 2.97 (dq, 1H), 1.30 (d, 3H)  87 A13-cis

42 ¹H NMR (DMSO-d₆) δ: 9.35 (d, 1H), 9.09 (dd, 1H), 8.75 (dd, 1H), 8.37(s, 1H), 8.27 (dt, 1H), 8.00 (t, 1H), 7.83-7.74 (m, 4H), 7.58- 7.50 (m,2H), 7.44-7.37 (m, 2H), 7.33 (dtd, 3H), 5.71 (d, 1H), 4.77-4.71 (m, 1H),3.19 (p, 1H), 1.12 (d, 3H)  88 A13-cis

41 ¹H NMR (DMSO-d₆) δ: 9.73 (d, 1H), 9.00 (d, 2H), 8.36 (d, 1H), 7.98(d, 1H), 7.77 (tq, 4H), 7.71 (t, 1H), 7.53-7.47 (m, 1H), 7.44- 7.34 (m,3H), 7.34-7.28 (m, 2H), 5.80 (d, 1H), 4.72 (s, 1H), 3.24- 3.16 (m, 1H),1.12 (d, 3H)  89 A21

41 ¹H NMR (DMSO-d₆) δ: 8.89 (dd, 1H), 8.82 (d, 1H), 8.72 (dd, 1H), 8.40(d, 1H), 8.08 (dt, 1H), 7.86- 7.78 (m, 4H), 7.51 (ddd, 1H), 7.48- 7.41(m, 3H), 7.39-7.34 (m, 2H), 7.28 (t, 2H), 7.19 7.13 (m, 1H), 4.45 (td,1H), 4.14 (td, 1H), 3.20-3.09 (m, 2H), 3.05 (dd, 1H), 1.47 (ddd, 1H),1.24 (dp, 1H), 0.52 (t, 3H)  90 A21

55 ¹H NMR (DMSO-d₆) δ: 9.26 (d, 1H), 8.98 (d, 2H), 8.40 (d, 1H),7.85-7.79 (m, 3H), 7.76 (dd, 1H), 7.71 (t, 1H), 7.48-7.39 (m, 3H),7.38-7.33 (m, 2H), 7.29- 7.23 (m, 2H), 7.17-7.11 (m, 1H), 4.47 (td, 1H),4.20 (td, 1H), 3.27- 3.20 (m, 1H), 3.09 (dd, 1H), 3.01 (dd, 1H), 1.41(ddt, 1H), 1.26- 1.15 (m, 1H), 0.46 (t, 3H)  92 A13- trans

73 ¹H NMR (DMSO-d₆) δ: 9.16 (s, 1H), 9.01 (d, 1H), 8.74 (dd, 1H), 8.34(s, 1H), 8.17 (dt, 1H), 7.78 (s, 1H), 7.77-7.71 (m, 3H), 7.58- 7.50 (m,2H), 7.46 (s, 1H), 7.43- 7.36 (m, 2H), 7.32 (d, 1H), 7.23 (td, 1H), 7.18(t, 1H), 5.93 (s, 1H), 4.36 (s, 1H), 3.01 (dq, 1H), 1.34 (d, 3H)  94A13-cis

12 ¹H NMR (DMSO-d₆) δ: 8.99 (d, 1H), 8.36 (d, 1H), 7.98-7.95 (m, 1H),7.81-7.72 (m, 3H), 7.48 (dt, 1H), 7.43-7.38 (m, 2H), 7.35 (dd, 1H), 7.30(dd, 2H), 6.66 (d, 1H), 5.77 (d, 1H), 4.67 (s, 1H), 3.93 (s, 2H), 3.13(dd, 1H), 1.08 (d, 3H)  97 A15-cis

60 1H NMR (DMSO-d₆) δ: 9.39 (d, 1H), 8.32 (d, 1H), 7.89 (d, 1H),7.81-7.71 (m, 3H), 7.68 (dd, 1H), 7.45-7.35 (m, 2H), 7.32- 7.23 (m, 2H),6.92-6.83 (m, 2H), 5.28 (d, 1H), 4.41 (td, 1H), 3.69 (s, 3H), 3.13 (p,1H), 1.80 (t, 3H), 1.09 (d, 3H)  98 A15- trans

24 ¹H NMR (DMSO-d₆) δ: 9.11 (d, 1H), 8.29 (d, 1H), 7.78-7.70 (m, 3H),7.68 (d, 1H), 7.48-7.35 (m, 3H), 7.29-7.20 (m, 2H), 6.83- 6.74 (m, 2H),5.19 (d, 1H), 4.11 (q, 1H), 3.65 (s, 3H), 2.84 (dq, 1H), 1.73 (t, 3H),1.26 (d, 3H) 104 A21

33 ¹H NMR (DMSO-d₆) δ: 8.48 (d, 1H), 8.39 (d, 1H), 7.84-7.77 (m, 4H),7.73 (d, 1H), 7.44 (t, 2H), 7.40 (dd, 1H), 7.36 (d, 2H), 7.29 (t, 2H),7.20 (t, 1H), 6.64 (d, 1H), 4.43 (td, 1H), 4.14 (td, 1H), 3.93 (s, 3H),3.19-3.11 (m, 1H), 3.10 (d, 1H), 2.93 (dd, 1H), 1.38 (dtd, 1H), 1.14(dp, 1H), 0.41 (t, 3H) 105 A21

25 ¹H NMR (DMSO-d₆) δ: 9.05 (s, 1H), 8.43 (d, 1H), 8.40 (d, 1H),7.84-7.80 (m, 3H), 7.79 (d, 1H), 7.48-7.41 (m, 3H), 7.38-7.33 (m, 2H),7.30 (t, 2H), 7.23-7.17 (m, 1H), 4.40 (td, 1H), 4.12 (td, 1H), 3.14-3.10(m, 1H), 3.09 (d, 1H), 3.04 (dd, 1H), 2.54 (s, 3H), 1.46 (dtd, 1H), 1.23(dp, 1H), 0.51 (t, 3H) 106 A21

46 ¹H NMR (DMSO-d₆) δ: 8.39 (s, 1H), 8.33 (d, 1H), 7.84-7.78 (m, 3H),7.76 (d, 1H), 7.48-7.38 (m, 3H), 7.34-7.28 (m, 4H), 7.23 (dq, 1H), 4.20(td, 1H), 3.98 (td, 1H), 3.02 (qd, 2H), 2.92 (dt, 1H), 1.45 (td, 1H),1.39 (dtd, 1H), 1.18 (dq, 1H), 0.73-0.63 (m, 4H), 0.42 (t, 3H) 107 A21

47 ¹H NMR (DMSO-d₆) δ: 8.90 (d, 1H), 8.39 (d, 1H), 7.86-7.77 (m, 3H),7.77 (d, 1H), 7.49-7.38 (m, 3H), 7.31 (d, 4H), 7.23 (tt, 1H), 4.23 (td,1H), 4.06 (td, 1H), 3.12 (ddd, 1H), 3.06 (dd, 1H), 2.99 (dd, 1H), 1.63(t, 3H), 1.38 (dtd, 1H), 1.20 (dp, 1H), 0.48 (t, 3H) 108 A17- trans

27 ¹H NMR (DMSO-d₆) δ: 8.56 (d, 1H), 8.34 (s, 1H), 7.81 (d, 1H), 7.78(ddd, 2H), 7.73 (d, 1H), 7.48 (dd, 1H), 7.44-7.40 (m, 2H), 6.96 (d, 1H),6.85 (dd, 1H), 5.38 (d, 1H), 4.16 4.09 (m, 1H), 2.76 (dq, 1H), 1.58(ddd, 1H), 1.24 (d, 3H), 0.75-0.70 (m, 3H), 0.68 (td, 1H) 109 A17- trans

33 ¹H NMR (DMSO-d₆) δ: 9.47 (d, 1H), 9.01 (dd, 2H), 8.35 (d, 1H),7.80-7.77 (m, 3H), 7.75 (d, 1H), 7.73 (td, 1H), 7.47 (dd, 1H), 7.45-7.39 (m, 2H), 6.98 (d, 1H), 6.83 (d, 1H), 5.63 (d, 1H), 4.48 (td, 1H),3.02 (dq, 1H), 1.29 (d, 3H) 110 A17- trans

31 ¹H NMR (DMSO-d₆) δ: 8.62 (d, 1H), 8.35 (d, 1H), 7.81-7.76 (m, 4H),7.74 (dt, 1H), 7.45 (dd, 1H), 7.45-7.39 (m, 2H), 6.96 (d, 1H), 6.82 (d,1H), 6.61 (d, 1H), 5.56 (d, 1H), 4.42 (td, 1H), 3.94 (s, 3H), 2.94 (dq,1H), 1.25 (d, 3H) 111 A17- trans

36 ¹H NMR (DMSO-d₆) δ: 9.11 (d, 1H), 9.06 (dd, 1H), 8.76 (dd, 1H), 8.36(d, 1H), 8.22 (dt, 1H), 7.85 (d, 1H), 7.80 7.75 (m, 3H), 7.56 (dd, 1H),7.52 (dd, 1H), 7.45- 7.39 (m, 2H), 7.02 (d, 1H), 6.85 (dd, 1H), 5.57 (d,1H), 4.40 (td, 1H), 2.95 (dq, 1H), 1.32 (d, 3H) 112 A13- trans

32 ¹H NMR (DMSO-d₆) δ: 8.54 (d, 1H), 8.31 (s, 1H), 7.77-7.68 (m, 3H),7.43 (s, 2H), 7.42-7.35 (m, 2H), 7.33 (d, 1H), 7.19 (dt, 2H), 5.81 (s,0H), 4.04 (s, 0H), 2.85 (p, 1H), 1.55 (p, 1H), 1.26 (d, 3H), 0.72-0.64(m, 3H), 0.61 (s, 1H) 113 A17- trans

28 ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 8.70 (d, 1H), 8.35 (d, 1H), 7.84(d, 1H), 7.80-7.76 (m, 2H), 7.75 (d, 1H), 7.50 (dd, 1H), 7.45- 7.39 (m,2H), 7.01 (d, 1H), 6.86 (d, 1H), 5.53 (d, 1H),4.35 (q, 1H), 2.91 (dq,1H), 2.60 (s, 3H), 1.31 (d, 3H) 115 A19

51 ¹H NMR (DMSO-d₆) δ: 8.55 (d, 1H), 8.32 (t, 1H), 7.80-7.73 (m, 3H),7.70 (dd, 1H), 7.48-7.44 (m, 2H), 7.44-7.40 (m, 2H), 6.15 (d, 1H), 5.17(d, 1H), 4.21 (td, 1H), 3.68 (s, 3H), 2.71 2.63 (m, 1H), 1.56 (ddd, 1H),1.26 (d, 3H), 0.72-0.65 (m, 4H) 116 A19

35 ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.67 (d, 1H), 8.33 (d, 1H),7.80-7.73 (m, 3H), 7.71 (dt, 1H), 7.50-7.45 (m, 2H), 7.45- 7.38 (m, 2H),6.19 (d, 1H), 5.30 (d, 1H), 4.43 (td, 1H), 3.68 (s, 3H), 2.82 (dq, 1H),2.59 (s, 3H), 1.33 (d, 3H) 117 A19

41 ¹H NMR (DMSO-d₆) δ: 8.54 (d, 1H), 8.32 (d, 1H), 7.80-7.74 (m, 3H),7.73-7.68 (m, 2H), 7.47- 7.42 (m, 1H), 7.44-7.38 (m, 3H), 6.59 (dd, 1H),6.20 (d, 1H), 5.35 (d, 1H), 4.52 (td, 1H), 3.93 (d, 3H), 3.65 (d, 3H),2.85 (dq, 1H), 1.27 (d, 3H) 118 A19

29 ¹H NMR (DMSO-d₆) δ: 9.10 (d, 1H), 9.04 (dd, 1H), 8.74 (dd, 1H), 8.33(d, 1H), 8.21 (dt, 1H), 7.81- 7.74 (m, 3H), 7.74-7.69 (m, 1H), 7.57-7.52(m, 1H), 7.52-7.46 (m, 2H), 7.45-7.38 (m, 2H), 6.21 (d, 1H), 5.35 (d,1H), 4.49 (q, 1H), 3.67 (s, 3H), 2.85 (p, 1H), 1.34 (d, 3H) 119 A19

44 ¹H NMR (DMSO-d₆) δ: 9.41 (d, 1H), 8.99 (dd, 2H), 8.33 (d, 1H),7.80-7.68 (m, 5H), 7.48-7.38 (m, 4H), 6.23 (t, 1H), 5.41 (dd, 1H), 4.59(td, 1H), 3.64 (d, 3H), 2.98-2.83 (m, 1H), 1.31 (dd, 3H) 120 A19

48 ¹H NMR (DMSO-d₆) δ: 9.14 (d, 1H), 8.32 (d, 1H), 7.81-7.71 (m, 3H),7.71 (d, 1H), 7.50-7.36 (m, 4H), 6.16 (d, 1H), 5.25 (d, 1H), 4.29 (td,1H), 3.68 (s, 3H), 2.78 (dq, 1H), 1.75 (t, 3H), 1.31 1.14 (m, 3H) 123A17- trans

35 ¹H NMR (DMSO-d₆) δ: 9.18 (d, 1H), 8.35 (d, 1H), 7.81-7.76 (m, 3H),7.74 (d, 1H), 7.46 (dd, 1H), 7.44-7.39 (m, 2H), 7.00 (d, 1H), 6.86 (d,1H), 5.46 (d, 1H), 4.20 (q, 1H), 2.89 (dq, 1H), 1.77 (t, 3H), 1.26 (d,3H) 124 A17-cis

24 ¹H NMR (DMSO-d₆) δ: 8.76 (d, 1H), 8.36 (d, 1H), 7.99 (dd, 1H),7.83-7.76 (m, 3H), 7.72 (dd, 1H), 7.46-7.38 (m, 2H), 6.99- 6.92 (m, 2H),5.42 (d, 1H), 4.51 (ddd, 1H), 3.14 (p, 1H), 1.70 (tt, 1H), 1.11 (d, 3H),0.80-0.67 (m, 4H) 125 A17-cis

19 ¹H NMR (DMSO-d₆) δ: 9.45 (d, 1H), 8.37 (d, 1H), 7.95 (d, 1H),7.84-7.74 (m, 3H), 7.67 (dd, 1H), 7.47-7.37 (m, 2H), 7.01 (d, 1H), 6.95(d, 1H), 5.58 (d, 1H), 4.56 (td, 1H), 3.22 (p, 1H), 1.82 (t, 3H), 1.09(d, 3H) 133 A15- trans

33 ¹H NMR (DMSO-d₆) δ: 8.54 8.49 (m, 1H), 8.29 (d, 1H), 7.78-7.71 (m,3H), 7.67 (dd, 1H), 7.47 (dd, 1H), 7.43-7.36 (m, 2H), 7.27- 7.21 (m,2H), 6.81 6.75 (m, 2H), 5.11 (d, 1H), 4.03 (td, 1H), 3.65 (s, 3H), 2.71(dq, 1H), 1.56 (tt, 1H), 1.24 (d, 3H), 0.73-0.57 (m, 4H)

Human Glucocorticoid Receptor (hGR) Ligand-Binding Assay

The human lymphoblast cell line IM9 (ATCC, Bethesda, Md.) was cultivatedin RPMI 1640 media containing 10% fetal bovine serum, penicillin (100U/ml), streptomycin (100 μg/ml), and 2 mM L-glutamine at 370 and 7% CO2in a humidified incubator. Cells were centrifuged for 10 minutes at 1500g and were washed in PBS and repelleted. Cell were then resuspended inhomogenization buffer consisting of: 10 mM TES, 10 mM sodium molybdate,1 mM EDTA, pH 7.4, 20 mM 2-mercaptoethanol, and 10% glycerol. Disruptionof the cells was performed by nitrogen cavitation using 2×15 minutes at600 to 750 psi nitrogen in a N2 cavitator at 0° C. The cell preparationwas then centrifuged at 27,000 g for 15 minutes, and the resultantsupernatant (=cytosol of IM9 cells) was centrifuged at 103,000 g for 60minutes at 4° C. The amount of protein in the supernatant fraction wasdetermined using a BCA assay kit and aliquots were snap frozen in a dryice-acetone bath and stored at −70° C. Competitive binding assays weredone in duplicate in homogenization buffer with a total volume of 200μl. To this end, 1 mg of IM9 cytosol, 0.05 μCi (1.5 nM) of3H-dexamethasone and unlabeled Example compounds as competitor compoundsat 1 μM were mixed. The reaction was stopped after incubation at 0° C.for 16 to 18 hours by the addition of 100 μl of a charcoal-dextranmixture (2% activated charcoal, 0.5% dextran in 10 mM Tris, 1 mM EDTA,pH 7.4). Another incubation step at 0° C. for 10 minutes followed beforethe samples were centrifuged for 5 minutes at 8200 g. 100 μl of thesupernatant) was finally assayed for radioactivity by liquidscintillationspectrometry, and percentage inhibition of 3H-dexamethasonebinding was calculated.

GRE Agonist

The reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary(CHO) cell line (Leibniz Institute DSMZ—German Collection ofMicroorganisms and Cell Cultures GmbH: ACC-110) containing a fireflyluciferase gene under the control of the GR ligand binding domain fusedto the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integratedinto CHO cells. This cell line was established by stable transfection ofCHO cells with a GAL4-UAS-Luciferase reporter construct. In a subsequentstep the ligand binding domain of the GR cloned into plRES2-EGFP-GAL4containing the DNA binding domain of GAL4 from pFA-AT2 was transfected.This fusion construct activated firefly luciferase expression under thecontrol of a multimerized GAL4 upstream activation sequence (UAS). Thesignal of the emitted luminescence was recorded by the LIPR^(TETRA).This allowed for specific detection of ligand-induced activation of theGR and therefore for the identification of compounds with agonisticproperties. The GAL4/UAS reporter was premixed with a vector thatconstitutively expressed Renilla luciferase, which served as an internalpositive control for transfection efficiency.

The complete culture medium for the assay was:

-   -   DMEM F-12 (1:1) MIXTURE (LONZA cat. N^(o): BE04-687F/U1) 500 mL    -   5 mL of 100 mM Sodium Pyruvate (LONZA cat. N^(o): BE12-115E)    -   25 mL of 7.5% Sodium Bicarbonate (LONZA cat. N^(o) BE17-613E)    -   6.5 mL of 1 M Hepes (LONZA cat. N^(o): BE17-737E)    -   5 mL of 100× Penicillin/Streptomycin (LONZA cat. N^(o)        DE17-602E)    -   50 mL of Fetal Bovine Serum (Euroclone cat. N^(o) ECS 0180 L)    -   0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1)    -   0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)        Cryo-preserved CHO-Gal4/GR cells were suspended in complete        medium and 5000 cells/25 μl/well were seeded into the wells of        384-well polystyrene assay plates (Thermo Scientific, cat.        #4332) and cultured at 37° C., 5% CO₂ and 95% humidity. After 24        hours growth medium was carefully removed and replaced by 30 μl        Opti-MEM (GIBCO, cat. #31985062) as assay buffer. To test the        compounds an 8-point half-log compound dilution curve was        generated in 100% DMSO starting from a 2 mM stock and compounds        were then diluted 1:50 in Opti-MEM. 10 μl of compounds were then        added to the wells containing 30 μl Opti-MEM resulting in a        final assay concentration range from 10 μM to 0.003 μM in 0.5%        DMSO. Compounds were tested at 8 concentrations in quadruplicate        data points. Cells were incubated for 6 hour with compounds and        beclometasone (Sigma, cat. # Y0000351) as control compound at        37° C., 5% CO₂ and 95% humidity in a total volume of 40 μl.        Finally, cells were lysed with 20 μl of Triton/Luciferin        solution and the signal of the emitted luminescence was recorded        at the FLIPR^(TETRA) for 2 minutes.

The relative efficacy of a compound (% effect) was calculated based onthe full effect of the agonist beclometasone:

% effect=((compound−min)/(max−min))×100

[min=Opti-MEM only,max=beclometasone]

To calculate EC₅₀, max, min and slope factor for each compound aconcentration response curve was fitted by plotting % effect versuscompound concentration using a 4 parameter logistic equation:

y=A+(B−A)/(1+((1° C.)/x)D)

[A=min y,B=max y,C=log EC ₅₀ ,D=slope]

GRE Antagonist

The reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary(CHO) cell line (Leibniz Institute DSMZ—German Collection ofMicroorganisms and Cell Cultures GmbH: ACC-110) containing a fireflyluciferase gene under the control of the GR ligand binding domain fusedto the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integratedinto CHO cells. This cell line was established by stable transfection ofCHO cells with a GAL4-UAS-Luciferase reporter construct. In a subsequentstep the ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4containing the DNA binding domain of GAL4 from pFA-AT2 was transfected.This fusion construct activated firefly luciferase expression under thecontrol of a multimerized GAL4 upstream activation sequence (UAS). Thesignal of the emitted luminescence was recorded by the FLIPR^(TETRA).This allowed for specific detection of antagonistic properties ofcompounds by measuring the ligand-induced inhibition ofbeclometasone-activated GR. The GAL4/UAS reporter was premixed with avector that constitutively expressed Renilla luciferase, which served asan internal positive control for transfection efficiency.

The complete culture medium for the assay was:

-   -   DMEM F-12 (1:1) MIXTURE (LONZA cat. N^(o): BE04-687F/U1) 500 mL    -   5 mL of 100 mM Sodium Pyruvate (LONZA cat. N^(o): BE12-115E)    -   25 mL of 7.5% Sodium Bicarbonate (LONZA cat. N^(o) BE17-613E)    -   6.5 mL of 1 M Hepes (LONZA cat. N^(o): BE17-737E)    -   5 mL of 100× Penicillin/Streptomycin (LONZA cat. N^(o)        DE17-602E)    -   50 mL of Fetal Bovine Serum (Euroclone cat. N^(o) ECS 0180 L)    -   0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1)    -   0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)        Cryo-preserved CHO-Gal4/GR cells were suspended in complete        medium and 5000 cells/25 μl/well were seeded into the wells of        384-well polystyrene assay plates (Thermo Scientific, cat.        #4332) and cultured at 37° C., 5% CO₂ and 95% humidity. After 24        hours growth medium was carefully removed and replaced by 20 μl        Opti-MEM (GIBCO, cat. #31985062) as assay buffer. For testing        compounds an 8-point half-log compound dilution curve was        generated in 100% DMSO starting from a 2 mM stock and compounds        were then diluted 1:50 in Opti-MEM. To test the compounds in the        antagonist mode 10 μl of compounds were then added to the wells        containing 20 μl Opti-MEM and incubated for 10 min. After this        pre-incubation 10 μl of the reference agonist beclometasone        (Sigma, cat. # Y0000351) at an EC50 of 2.5 nM were added        resulting in a final assay concentration range from 10 μM to        0.003 μM in 0.5% DMSO in a total volume of 40 μl. Compounds were        tested at 8 concentrations in quadruplicate data points. Cells        were incubated for 6 hour with compounds and mifepristone as        control compound (Sigma, cat. # M8046) at 37° C., 5% CO₂ and 95%        humidity. Finally, cells were lysed with 20 μl of        Triton/Luciferin solution and the signal of the emitted        luminescence was recorded at the FLIPR^(TERA) for 2 minutes.

The relative efficacy of a compound (% effect) was calculated based onthe full effect of the antagonist mifepristone:

% effect=((compound−min)/(max−min))×−100

[min=Opti-MEM only,max=mifepristone]

To calculate IC₅₀, max, min and slope factor for each compound aconcentration response curve was fitted by plotting % effect versuscompound concentration using a 4 parameter logistic equation:

y=A+(B−A)/(1+((10C)/x)D)

[A=min y,B=max y,C=log IC ₅₀ ,D=slope]

Table summarizing biological data:

IC50 or EC50 % A < 100 nM, inhibition cmpd B = 100 nM-1 μM, hGR at # C =1 μM-15 μM 1 μM  1 A 99  2 B 91  3 A 98  4 B 95  5 B 95  6 B 97  7 C 96 8 n.a. 12  9 n.a. 86  10 n.a. 100  12 n.a. 83  13 n.a. 20  14 n.a. 84 15 n.a. 87  16 n.a. 30  17 n.a. 80  18 n.a. 29  21 n.a. 22  22 n.a. 18 24 n.a. 12  26 n.a. 28  30 n.a. 27  31 B n.d.  33 C n.d.  34a A n.d. 34b B n.d.  35a A n.d.  36a B n.d.  36b B n.d.  37 A n.d.  38a B n.d. 38b A n.d.  39a A n.d.  40a A n.d.  40b B n.d.  41b C n.d.  42a A n.d. 42b B n.d.  43a A n.d.  43b C n.d.  44a A n.d.  44b B n.d.  45a A n.d. 45b B n.d.  46 A n.d.  47 A n.d.  60 B n.d.  61 B n.d.  62 B n.d.  63 Bn.d.  64 A n.d.  65 A n.d.  66 A n.d.  67 A n.d.  68 B n.d.  69 A n.d. 70 A n.d.  71 B n.d.  72 A n.d.  73 A n.d.  74 B n.d.  75 A n.d.  76 An.d.  77 A n.d.  82 B n.d.  83 A n.d.  84 B n.d.  85 B n.d.  86 A n.d. 87 A n.d.  88 A n.d.  90 C n.d.  91 C n.d.  92 A n.d.  93 A n.d.  94 An.d.  95 A n.d.  96 A n.d.  98 A n.d. 100 A n.d. 101 B n.d. 104 C n.d.107 C n.d. 108 A n.d. 109 A n.d. 110 A n.d. 111 A n.d. 112 B n.d. 113 Bn.d. 114 B n.d. 120 C n.d. 121 A n.d. 123 A n.d. 124 A n.d. 125 A n.d.126 A n.d. 127 B n.d. 128 B n.d. 129 A n.d. 130 B n.d. 131 B n.d. 132 An.d. 133 B n.d. 134 B n.d. 135 A n.d. 136 A n.d. 137 A n.d. 138 B n.d.139a C n.d. 139b C n.d. 148 A n.d. 149 A n.d. 150 B n.d. 151 B n.d.“n.a.”: not active in the GR cell-based assays, neither in the agonisticnor in the antagonistic mode. “n.d.”: not determined.

Prophetic Examples

The prophetic examples summarized in the following table could besynthesized in analogy to Example 7 described above. The person skilledin the art would know how to select suitable intermediates in order toobtain any of the prophetic examples shown in the below table.

Proph. Ex. # Structure  48

 49

142

143

144

145

146

147

indicates data missing or illegible when filed

In any of the above tables, the example compounds wherein thesubstituents which are connected to the central pyrrolidone have adifferent relative orientation, e.g. phenyl moiety and methyl moiety up(“bold bond”,

) and amide moiety down (“hashed bond”,

) or vice versa, are the “trans” diastereomer which is a racemic mixtureof the two corresponding trans enantiomers.

1. A compound according to general formula (I):

wherein R₁ represents phenyl; —C₁₋₆-alkylene-phenyl; 5 or 6-memberedheteroaryl; —C₁₋₆-alkylene-(5 or 6-membered heteroaryl) or —C₁₋₁₀-alkyl;R_(1′) represents H; —C₁₋₁₀-alkyl; or —C₃₋₁₀-cycloalkyl; R₂ represents—C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;—C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-(3 to 7 memberedheterocycloalkyl); —C(═O)—C₁₋₆-alkylene-(3 to 7 memberedheterocycloalkyl); —C(═O)-phenyl; —C(═O)—C₁₋₆-alkylene-phenyl; —C(═O)-(5or 6-membered heteroaryl); —C(═O)—C₁₋₆-alkylene-(5 or 6-memberedheteroaryl); —S(═O)₁₋₂—C₁₋₁₀-alkyl; —S(═O)₁₋₂—C₃₋₁₀-cycloalkyl;—S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂-(3 to 7 memberedheterocycloalkyl); —S(═O)₁₋₂—C₁₋₆-alkylene-(3 to 7 memberedheterocycloalkyl); —S(═O)₁₋₂-phenyl; —S(═O)₁₋₂—C₁₋₆-alkylene-phenyl;—S(═O)₁₋₂-(5 or 6-membered heteroaryl); or —S(═O)₁₋₂—C₁₋₆-alkylene-(5 or6-membered heteroaryl); R₃ and R_(3′) independently from one anotherrepresent H; F; Cl; —C₁₋₁₀-alkyl; —C₃₋₆-cycloalkyl;—CH₂—C₃₋₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; —CH₂-(3 to 7membered heterocycloalkyl); —CH₂-phenyl; or —CH₂-(5 or 6-memberedheteroaryl); or R₃ and R_(3′) together with the carbon atom to whichthey are bound form a C₃₋₁₀-cycloalkyl; or 3 to 7 memberedheterocycloalkyl; R₄ represents -phenyl; —C₁₋₆-alkylene-phenyl; -5 or6-membered heteroaryl; or —C₁₋₆-alkylene-(5 or 6-membered heteroaryl);A, X, Y and Z independently from one another represent N or CH; whereinat least one of R_(1′), R₃ and R_(3′) is not H; wherein —C₁₋₁₀-alkyl and—C₁₋₆-alkylene-in each case independently from one another is linear orbranched, saturated or unsaturated; wherein —C₁₋₁₀-alkyl,—C₁₋₆-alkylene-, —C₃₋₁₀-cycloalkyl and 3 to 7 membered heterocycloalkylin each case independently from one another are unsubstituted or mono-or polysubstituted with one or more substituents selected from —F; —Cl;—Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;—C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH₂;—C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃; —OCF₂H;—OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl; —O—C(═O)—C—₆-alkyl;—O—C(═O)—O—C₁₋₆-alkyl; —O—(CO)—NH(C₁₋₆-alkyl); —O—C(═O)—N(C₁₋₆-alkyl)₂;—O—S(═O)₂—NH₂; —O—S(═O)₂—NH(C₁₋₆-alkyl); —O—S(═O)₂—N(C₁₋₆-alkyl)₂; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—NH—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—NH₂; —NH—C(═O)—NH(C₁₋₆-alkyl);—NH—C(═O)—N(C₁₋₆-alkyl)₂; —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-C(═O)—NH₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂OH; NH—S(═O)₂—C₁₋₆-alkyl;—NH—S(═O)₂—O—C₁₋₆-alkyl; —NH—S(═O)₂—NH₂; —NH—S(═O)₂—NH(C₁₋₆-alkyl);—NH—S(═O)₂N(C₁₋₆-alkyl)₂; —N(C₁₋₆-alkyl)-S(═O)₂—OH;—N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-S(═O)₂—NH₂; —N(C₁₋₆-alkyl)-S(═O)₂—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂;—S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—OH;—S(═O)₂—O—C₁₋₆-alkyl; —S(═O)₂—NH₂; —S(═O)₂—NH(C₁₋₆-alkyl);—S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl; 5 or 6-membered heteroaryl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —O-phenyl;—O-(5 or 6-membered heteroaryl); —C(═O)—C₃₋₆-cycloalkyl; —C(═O)-(3 to6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5 or 6-memberedheteroaryl); —S(═O)₂—(C₃₋₆-cycloalkyl); —S(═O)₂-(3 to 6-memberedheterocycloalkyl); —S(═O)₂-phenyl or —S(═O)₂-(5 or 6-memberedheteroaryl); wherein phenyl and 5 or 6-membered heteroaryl in each caseindependently from one another are unsubstituted or mono- orpolysubstituted with one or more substituents selected from —F; —Cl;—Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;—C₁₋₄-alkylene-CF₃; —C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂;—C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH(OH);—C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O;—OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —NH—C(═O)—NH₂;—NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂—C₁₋₆-alkyl; —SCF₃;—S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—NH₂;—S(═O)₂—NH(C₁₋₆-alkyl); —S(═O)₂—N(C₁₋₆-alkyl)₂—C₃₋₆-cycloalkyl;—C₁₋₄-alkylene-C₃₋₆-cycloalkyl; 3 to 6-membered heterocycloalkyl;—C₁₋₄-alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or6-membered heteroaryl; in the form of the free compound or aphysiologically acceptable salt thereof; with the proviso that thefollowing compounds are excluded:N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide;N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide;N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide;N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxylicacid amide;N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide;N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylicacid amide; andN-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylicacid amide.
 2. The compound according to claim 1, which has astereochemistry according to general formula (II) or (VI):


3. The compound according to claim 1, wherein A represents N, Xrepresents CH, represents CH; and Z represents CH; PGP- or A representsN, X represents N, Y represents CH; and Z represents CH; or A representsN, X represents CH, Y represents N; and Z represents CH; or A representsN, X represents CH, Y represents CH; and Z represents N; or A representsN, X represents N, Y represents N; and Z represents CH; or A representsN, X represents N, Y represents CH; and Z represents N; or A representsN, X represents CH, Y represents N; and Z represents N; or A representsN, X represents N, Y represents N; and Z represents N; or A representsCH, X represents CH, Y represents CH; and Z represents CH; or Arepresents CH, X represents N, Y represents CH; and Z represents CH; orA represents CH, X represents CH, Y represents N; and Z represents CH;or A represents CH, X represents CH, Y represents CH; and Z representsN; or A represents CH, X represents N, Y represents N; and Z representsCH; or A represents CH, X represents N, Y represents CH; and Zrepresents N; or A represents CH, X represents CH, Y represents N; and Zrepresents N; or A represents CH, X represents N, Y represents N; and Zrepresents N.
 4. The compound according to claim 1, wherein R₁represents phenyl; and/or R_(1′) represents H, CH₃ or cyclopropyl. 5.The compound according to claim 1, wherein R₂ represents—C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;—C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-(3 to 7 memberedheterocycloalkyl); —C(═O)-(5 or 6-membered heteroaryl);—S(═O)₂—C₁₋₁₀-alkyl; —S(═O)₂—C₃₋₁₀-cycloalkyl;—S(═O)₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₂-(3 to 7 memberedheterocycloalkyl); or —S(═O)₂-(5 or 6-membered heteroaryl).
 6. Thecompound according to claim 1, wherein R₃ and R_(3′) both represent—C₁₋₁₀-alkyl.
 7. The compound according to claim 1, wherein R₄represents -phenyl; or 5 or 6-membered heteroaryl.
 8. The compoundaccording to claim 1, wherein R₁ represents phenyl, unsubstituted ormono- or disubstituted with substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —OCH₃, —CH₃, —CF₃,—CN, and cyclopropyl.
 9. The compound according to claim 1, wherein R₂represents —C(═O)—C₁₋₁₀-alkyl, unsusbtituted or mono- or disubstitutedwith substituents independently of one another selected from the groupconsisting of —F, —Cl, and —Br; —C(═O)-cyclopropyl, unsubstituted ormono- or disubstituted with substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and—OCH₃; —C(═O)-2-tetrahydrofuranyl, unsubstituted; —C(═O)-(5- to6-membered heteroaryl), wherein said 5- to 6-membered heteroaryl isselected from the group consisting of thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, 1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, and isothiazolyl,wherein in each case said 5- to 6-membered heteroaryl is unsubstitutedor mono- or disubstituted with substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, ═O,and —OCH₃; —S(═O)₂—C₁₋₁₀-alkyl, unsubstituted; —S(═O)₂-cyclopropyl,unsubstituted; —S(═O)₂—CH₂-cyclopropyl, unsubstituted;—S(═O)₂₋₂-tetrahydrofuranyl, unsubstituted; or —S(═O)₂-(5- to 6-memberedheteroaryl), wherein said 5- to 6-membered heteroaryl is selected fromthe group consisting of thiazolyl, pyrazolyl, oxazolyl, isoxazolyl,1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, and isothiazolyl, wherein in eachcase said 5- to 6-membered heteroaryl is unsubstituted or mono- ordisubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, ═O, and—OCH₃.
 10. The compound according to claim 1, wherein R₃ and R_(3′) bothrepresent —CH₃.
 11. The compound according to claim 1, wherein R₄represents phenyl, unsubstituted or mono- or disubstituted withsubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃; 5- to 6-memberedheteroaryl selected from the group consisting of pyridyl, pyrazolyl, andpyrimidinyl, wherein in each case said 5- to 6-membered heteroaryl isunsubstituted or mono- or disubstituted with substituents independentlyof one another selected from the group consisting of ═O, —F, —Cl, —Br,—CH₃, —CF₃, —CN, and —OCH₃.
 12. The compound according to claim 1,wherein R₁ represents phenyl, unsubstituted or mono- or disubstitutedwith substituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —CH₃, and —OCH₃; and/or R_(1′) represents H,CH₃, or cyclopropyl; and/or R₂ represents —C(═O)—C₁₋₆-alkyl;—C(═O)-cyclopropyl; or —C(═O)-(5- to 6-membered heteroaryl),unsubstituted or mono- or disubstituted with substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br, and—CH₃; and/or R₄ represents fluoro-phenyl or N-methyl-2-oxo-pyridyl. 13.The compound according to claim 1 selected from the group consisting of:1N-[(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 2N-[(2S,3R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 3N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylicacid amide; 42,2-Difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide;5N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-indol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylicacid amide; 6N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carboxylicacid amide; 7N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylicacid amide; 8N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide;9N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoro-propionamide;102,2-Difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide;12N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 13N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylicacid amide; 14N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxylicacid amide; 15N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylicacid amide; 16N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 17N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylicacid amide; 18N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylicacid amide; 21N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-oxazole-5-carboxylicacid amide; 22N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylicacid amide; 24N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-5-carboxylicacid amide; 26N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-2-carboxylicacid amide; 30N-[rac-(6R,7S)-5-[1-(1-Methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylicacid amide; 31N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylicacid amide; 32N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylicacid amide; 33N-[rac-(6R,7S)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl]-cyclopropanecarboxylicacid amide; 34aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)methanesulfonamide; 34bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)methanesulfonamide; 35aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanesulfonamide; 35bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanesulfonamide; 36aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)oxazole-5-carboxamide;36bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)oxazole-5-carboxamide;37N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide;38aN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide;38bN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methylthiazole-5-carboxamide;39aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide;39bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-5-methylthiazole-4-carboxamide;40aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide;40bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-3-methylisoxazole-4-carboxamide;41aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide;41bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide;42aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)nicotinamide;42bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)nicotinamide;43aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)pyrimidine-2-carboxamide;43bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)pyrimidine-2-carboxamide;44aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide;44bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2-methyloxazole-5-carboxamide;45aN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide;45bN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-4-methyloxazole-5-carboxamide;46N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 47N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;48N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(3-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 49N-[rac-(2R,3S,4S)-2-(4-Fluorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 60N-[rac(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 61N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-methanesulfonicacid amide; 62N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 63N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 64N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 65N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 66N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 67N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 68N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 69N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 70N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 71N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 72N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 73N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 74N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 75N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 76N-[rac-(2R,3S,4R)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 772,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide;78N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 79N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;802,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide;812,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin-3-yl]-propionamide;82N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 83N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 84N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 85N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 86N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 87N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 88N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 89N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 90N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 91N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 92N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 93N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 94N-[rac-(2R,3S,4R)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 95N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;96N-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;972,2-Difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide;982,2-Difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-propionamide;99N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 1002,2-Difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide;101N-[rac-(2R,3S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 1022,2-Difluoro-N-[rac-(2R,3S)-2-methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide;103N-[rac-(2R,3S)-2-Methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 104N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 105N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 106N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 107N-[rac-(2R,3S,4S)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;108N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 109N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 110N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 111N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 112N-[rac-(2R,3S,4S)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 113N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 114N-[(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 115N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 116N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylicacid amide; 117N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 118N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyridine-3-carboxylicacid amide; 119N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylicacid amide; 1202,2-Difluoro-N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-propionamide;121N-[rac-(2R,3S,4S)-4-(Cyclopropyl-methyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 122N-[rac-(2S,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]-methanesulfonicacid amide; 123N-[rac-(2S,3S,4S)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;124N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 125N-[rac-(2S,3S,4R)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propionamide;126N-[rac-(2R,3S,4S)-4-Ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 127N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide,diastereomer 2; 128N-[rac-(2R,3R,4R)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 129N-[rac-(2R,3R,4S)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 130N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide,diastereomer 1; 131N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;132N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;133N-[rac-(2R,3S,4S)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylicacid amide; 134N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;135N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspiro[3.4]octan-8-yl)cyclopropanecarboxamide;136 N-(rac(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;137N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide;138N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;139N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;142N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;143N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;144N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide;145N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide;146N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide;147N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)oxetane-3-carboxamide;148N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;149N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide;150N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenyl-4-(thiazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide;and 151N-((2S,3S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide;in each case in the form of the free compound or a physiologicallyacceptable salt thereof.
 14. A pharmaceutical dosage form comprising acompound according to claim
 1. 15. A method for the treatment and/orprophylaxis of pain and/or inflammation in a patient in need thereof,said method comprising administering to said patient an effective amounttherefor of at least one compound according to claim 1.